Preliminary Assessment of Health Risks
to Garment Workers and Certain Home Residents
from Exposure to Formaldehyde
DRAFT
May 1985
Risk Analysis Branch
Existing Chemical Assessment Division
Office of Toxic Substances
This document is a preliminary draft and has not been formally-
peer and administratively reviewed within the office of
Pesticides and Toxic Substances, U.S. Environmental Protection
Agency. Therefore, the document does not represent the opinion
of the Office of the Agency.
-------
Table of Contents
Pace
List of Tables iv
List of Figures vii
1. Executive Summary 1-1
1.1. Carcinogenic Effects 1-1
1.2. Other Effects 1-2
1.3. Exposure 1-4
1.4. Risk Estimates 1-5
2. Introduction 2-1
3. Physical-Chemical Properties 3-1
4. Hazard of Carcinogenic Effects 4-1
4.1. Long- and Short-Term Animal Tests 4-1
4.2. Data Selection for Quantitative Analysis 4-17
4.2.1. Polypoid Adenomas/Other Tumors
Ooserved 4-17
4.3. Short-Term Tests: Mutayenicity/Genotoxicity .... 4-23
4.4. Other Effects/Defense Mechanisms 4-30
4.4.1. Introduction 4-30
4.4.2. Sensory Irritation 4-31
4.4.3. 'Cell Proliferation, Cytotoxicity,
and the Mucous Layer 4-35
4.5. Metabolism and Pharmacokinetics 4-50
4.5.1. Absorption 4-50
4.5.2. Pnarmacokinetics 4-51
4.5.3. Summary 4-59
4.6. Structure-Activity Relationships 4-60
4.7. Epidemiologic Studies 4-64
4.7.1. Review of Studies 4-67
4.7.2. Conclusion 4-92
-------
4.8. Weight-of-Evidence 4-94
4.8.1. Assessment of Human Evidence 4-94
4.8.2. Assessment of Animal Studies 4-95
4.8.3. Categorization of overall Evidence 4-10U
5. Hazard of Noncarcinogenic Effects 5-1
5.1. HCHO-Related Effects of the Eyes and
Respiratory system 5-1
5.1. .1» Eye ,..>*,,.,**.,.,.,»>*<... 5-2
5.J.2. olfactory System >,*,,.,.., 5-3
5.1.3. Upper Airway Irritation 5-4
5.1.4. Lower Airway and Pulmonary Effects 5-4
5.1.5. Asthma 5-5
5.1.6. Summary 5-6
5.2. Irritation/Sensitization—Dermal and Systemic ... 5-7
5.3. Cellular Changes 5-10
5.4. Central Nervous System Effects 5-14
5.4.1. Neurochemical Changes 5-15
5.4.2. Human Studies , 5-15
5.4.3. Conclusion 5-18
5.5. Developmental and Reproductive Effects 5-18
5.5.1. Animal Studies 5-18
5.5.2. Human Data 5-20
5.5.3. Conclusion 5-22
5.6. Effects on Visceral Organs 5-24
f:
6. Exposure Assessment 6-1
6.1.' Introduction 6-1
6.2. Estimates of Current Human Exposure 6-3
6.3. Populations at Risk 6-4
. 6.3.1. Home Residents 6-4
? - 6.3.2. Garment Workers 6-5
6.3.3. Summary 6-5
6.4. Sources of HCHO in Categories of Concern 6-6
6.4.1. Homes 6-6
6.4.2. Garment Manufacture 6-8
11
-------
6.5. HCHO Levels in Homes and Garment
Manufacturing bites 6-9
6.5.1. Manufactured Homes 6-9
6.5.2. Conventional Homes 6-18
6.5.3. Garment Worker Exposure 6-25
6.6. Summary 6-33
7. Estimates of Cancer Risk 7-1
7.1. Risk Estimates Based on
Squamous Cell Carcinoma Data 7-1
7.2. Risk Estimates Based on Polypoid
Adenoma Data 7-8
7.3. Uncertainty in Risk Estimates 7-10
7.4. Presentation of Risk Estimates 7-15
7.4.1. Separate Risk Estimates Derived
From Squamous Cell Carcinoma and
Polypoid Adenoma Data 7-15
7.4.2. Calculate Risks Separately But
Add the Risks 7-18
7.4.3. Summary 7-22
8. Estimates of Noncancer Risks 8-1
8.1. Introduction 8-1
8.2. Studies Reviewed 8-1
8.3. Limitations of Studies 8-15
8.3.1. Study Design Limitations 8-15
8.3.2. Bias Limitations 8-16
8.4. Results 8-16
8.5. Discussion 8-20
9. Risk Characterization 9-1
y.l. Cancer 9-1
9.2. Other Effects 9-5
9.3. Summary 9-8
10. References 10-1
111
-------
List of Tables
Table Title page
4-1 Summary of Neoplastic Lesions in Nasal 4-2
Cavity of Fischer 344 Rats Exposed to
Formaldehyde Gas
4-2 Summary of Neoplastic Lesions in the Nasal 4-9
Cavity of Sprague-Dawley Rats
4-3 • Incidence of Polypoid Adenoma as Reported 4-18
by PWG
4-4 Effect of Formaldehyde Exposure on Cell 4-36
Proliferation in Level B of the Nasal
Passages
4-5 Effect of the Time of 3H-Thymidine Pulse 4-37
on Cell Replication After HCHu Exposure to
Rat
4-6 Effect of HCHO Concentration vs. Cumulative 4-38
Exposure on Cell Turnover in Rats (Level B)
*
4-7 Effect of HCHO Concentration vs. Cumulative 4-38
Exposure on Cell Turnover in Rats (Level A)
4-8 Effect of HCHU Concentration vs. Cumulative 4-39
Exposure on Cell Turnover in Mice (Level A)
4-9 Frequency of Squamous Metaplasia in Level 2 4-42
of the Rat Nasal Cavity
4-10 Incidence of Lesions Other Than Tumors in 4-43
the Larnyx of Rats Exposed to Acetaldehyde
I Numeric]
4-11 Incidence of Epidermoid and Adenoid 4-43
Squamous Carcinomas in Rats Exposed to
bexamethylphosphocamide
-4-12 Inhalation Carcinogenicity of Acetaldehyde 4-65
in Rats—Summary of Nasal Tumors
4-13 Summary of Studies Relevant to Formaldehyde 4-68
4-14 Power Calculations for SMR Studies . 4-69
IV
-------
Taole Title Page
4-15 Conditional Power Calculations for PMR 4-70
Stud ies
4-16 Power Calculations for Case-Control Studies 4-71
5-1 Reported Health Effects of Formaldehyde 5-1
at Various Concentrations
5-2 Delayed Type Hypersensitivity (Human) 5-9
Due to Low Levels of Formaldehyde
5-3 • Significant Findings in Nasal Turbinates 5-12
in Rats
5-4 Significant Findings in Nasal Turbinates 5-12
in Monkeys
5-5 Total Incidence by Groups of Monkeys 5-12
6-1 Populations at Risk 6-5
6-2 Summary of Formaldehyde Concentrations 6-12
in Complaint Mobile Homes in Kentucky
from September 1979 Through December
1980
6-3 Potential Effects of Temperature and 6-15
Relative Humidity Changes on Formaldehyde
Air Concentrations
6-4 Frequency of Observations Found in 6-16
Concentration Intervals by Clayton
Environmental Consultants
6-5 Frequency of Observations Found in 6-17
Concentration Intervals by Wisconsin
Division of Health
6-6 Comparison of Non-UFFI Canadian Homes 6-20
by Average Formaldehyde Concentration
6-7 ORNL/CPSC Mean Formaldehyde Concentrations 6-22
(ppmr) as a Function of Age and Season
(Outdoor Means Are Less Than 25 ppb
Detection Limit)
-------
Table Title page
6-8 Frequency Distribution of Formaldehyde 6-24
Levels in Washington Conventional Non-
UFFI Homes
6-9 Pre-1980 Monitoring Data for Garment 6-27
Manufacturing and Closely Related
Industries
6-10 Recent Monitorign Data for Formaldehyde 6-28
in the Garment Manufacturing Industry
6-11 - S'loSH Monitoring Results - Ranges by 6-31
Deparment
6-12 Formaldehyde Concentration Levels 6-32
(ppm) - Garment Manufacturing
7-1 Estimated Individual and Population Risks 7-7
Based Upon Squamous Cell Carcinoma Data
From CUT Study. Population Risks (number
of excess tumors) Appear in Parentheses
Below Individual Risk Estimates
7-2 Risk Based on Polypoid Adenoma Data 7-9
8-1 Summary of Dose-Response Data for 8-2
Non-Carcinogenic Health Effects of
Formaldehyde
8-2 Summary of Selected Cross Sectional 8-9
Studies
8-3 Summary of Selected Controlled Human 8-13
Studies
8-4 Exposure Ranges for Selected Endpoints 8-23
9-1 Summary of Cancer and Noncancer Risks 9-9
VI
-------
List of Figures
Figures Title Page
4-1 Frequency of squamous metaplasia in the 4-4
nasal cavity of Fischer 344 rats exposed
to 2.0 ppm (top), 5.6 ppm (middle), or
14.3 ppm (bottom) of formaldehyde gas for
24 months. Nasal cavity Levels I, II, IV,
and V were not evaluated at the 6- and 12-
month interim sacrifices in the 14.3 ppm
exposure group.
4-2 Frequency of squamous metaplasia in the 4-6
nasal cavity of B6C3F^ mice exposed to
14.3 ppm of formaldehyde gas.
4-3 Drawing indicating the level of sections 4-36
from the nasal passages of rats and mice.
4-4 Simplified reaction sequence from drug 4-55
N-demethylation (cytochrome-P-450-dependent
monooxygenase) to HCHO, formate, and C02
production (from Waydhas et al., 1978).
Reactions are: la, HCHU dehydrogenase (GSH);
ID, aldehyde dehydrogenase; Ic, catalase
(peroxidatic mode); 2a, 10-formyltetrahydro-
folate sythetase; 2b, 10-formyltetrahydro-
folate dehydrogenase; 2c, catalase
(peroxidatic mode).
4-5 Tetrahydrofolic acid pathway and 1-carbon 4-57
transfer for HCHO metaoolism.
4-6 Overall metabolism of HCHO. 4-59
6-1 Levels of Mobile Homes Corresponding to 6-11
: Year of Manufacture.
6-2 Frequency of Formaldehyde Levels, By 6-13
Home Age, Exceeding 1.0, 0.4, and 0.2
ppm In Clayton and Wisconsin Data
Combined.
6-3 Frequency Distribution of Levels in 6-26
Conventional Homes.
VI 1
-------
1. EXECUTIVE SUMMARY
Since 1979, when the preliminary results from the Chemical
Industry Institute of Toxicology (CUT) study indicated the
formation of nasal cancer in rats, much attention has been
focused on the potential human carcinogenicity of formaldehyde
(HCHO). However, it was HCHO's acute effects that initially
prompted the Federal government's effort to control HCHO
exposures from Urea-HCHO foam (UFFI) installations and high HCHO
emitting building materials in manufactured homes. Although
attention has shifted to the potential human carcinogenicity,
HCHO's other effects have the most immediate impact on persons
and continue to generate a substantial number of consumer
complaints. Consequently, this risk assessment will address
HCHO's carcinogenic and noncarcinoyenic effects.
1.1. Carcinogenic Effects
Formaldehyde (HCHO) is carcinogenic by inhalation in males
and females of one strain of rat and in males of another strain,
and there is evidence of its carcinogenicity in mice. In the
CUT study (iKern et al., 1983), HCHO produced tumors of a type
with very low background rates after a short latency period and
with a dose-response relationship. The same malignant tumors
were also seen in the Albert Et al. (1982) and Tobe et al. (1985)
studies. Negative studies in other species, in this case the
hamster, do not reduce the weight given to the positive findings.
Other data support the bioassay data. HCHO's mutagenic
activity has been shown in a number of tests and it has been
1-1
-------
shown to be a weak promoter on mouse skin. HCHO has been shown
to be capable of eliciting benign tumors at concentrations which
fall within human exposure ranges and malignant tumors within'an
order of magnitude above estimated human exposure. In addition,
other aldehydes which are structurally similar to HCHO, such as
acetaldehyde, malondialdehyde, and glycidaldehyde, have been
shown to have oncogenic potential., Finally, ths existing
-------
Preliminary Assessment of Health Risks
to Garment Workers and Certain Hone Residents
from Exposure to Formaldehyde
DRAFT
May 1985
Risk Analysis Branch
Existing Chemical Assessment Division
Office of Toxic Substances
This document is a preliminary draft and has not been formally
peer and administratively reviewed within the Office of
Pesticides and Toxic Substances, U.S. Environmental Protection
Agency. Therefore, the document does not represent the opinion
of the Office of the Agency.
-------
Table of Contents
Page
List of Tables iv
List of Figures vii
1. Executive Summary 1-1
1.1. Carcinogenic Effects 1-1
1.2. Other Effects 1-2
1.3. Exposure 1-4
1.4. Risk Estimates 1-5
2. Introduction 2-1
3. Physical-Chemical Properties 3-1
4. Hazard of Carcinogenic Effects 4-1
4.1. Long- and Short-Term Animal Tests 4-1
4.2. Data Selection for Quantitative Analysis 4-17
4.2.1. Polypoid Adenomas/Other Tumors
Ooserved 4-17
4.3. Short-Term Tests: Mutagenicity/Genotoxicity .... 4-23
4.4. Other Effects/Defense Mechanisms 4-30
4.4.1. Introduction 4-30
4.4.2. Sensory Irritation 4-31
4.4.3. Cell Proliferation, Cytotoxicity,
and the Mucous Layer 4-35
4.5. Metabolism and Pharmacokinetics 4-50
4.5.1. Absorption 4-50
4.5.2. Pharmacokinetics 4-51
4.5.3. Summary 4-59
4.6. structure-Activity Relationships 4-60
4.7. Epidemiologic Studies 4-64
4.7.1. Review of Studies 4-67
4.7.2. Conclusion 4-92
-------
4.d. Weight-of-Evidence 4-94
4.8.1. Assessment of Human Evidence ............ 4-94
4.8.2. Assessment of Animal Studies 4-95
4.8.3. Categorization of overall Evidence 4-100
5. Hazard of Noncarcinogenic Effects 5-1
5.1. HCHO-Related Effects of the Eyes and
Respiratory System 5-1
3 « A o i 3 fcjf ^ *»»»a«»»»»o-»od»&<><>»*»«*««»»«»»»»»«»»» O^ ^
5.1.2. olfactory System *.<.,.....<> 5-3
5.1.3. Upper Airway Irritation 5-4
5.1.4. Lower Airway and Pulmonary Effects 5-4
5.1.5. Asthma 5-5
5.1.6. summary 5-6
5.2. Irritation/Sensitization—Dermal and Systemic ... 5-7
5.3. Cellular Changes 5-10
5.4. Central Nervous System Effects 5-14
5.4.1. Meurochemical Changes 5-15
5.4.2. Human Studies 5-15
5.4.3. Conclusion 5-18
5.5. Developmental and Reproductive Effects 5-18
5.5.1. Animal Studies 5-18
5.5.2. Human Data 5-20
5.5.3. Conclusion . 5-22
5.6. Effects on Visceral Organs 5-24
6. Exposure Assessment 6-1
6.1. Introduction .................................... 6-1
6.2. Estimates of Current Human Exposure 6-3
6.3. Populations at Risk 6-4
6.3.1. Home Residents 6-4
6.3.2. Garment Workers 6-5
6.3.3. Summary 6-5
6.4. Sources of HCHO in Categories of Concern 6-6
6.4.1. Homes 6-6
6.4.2. Garment Manufacture 6-8
-------
List of Tables
Table Title page
4-1 Summary of Neoplastic Lesions in Nasal 4-2
Cavity of Fischer 344 Rats Exposed to
Formaldehyde Gas
4-2 Summary of Neoplastic Lesions in the Nasal 4-9
Cavity of Sprague-Dawley Rats
4-3 • Incidence of Polypoid Adenoma as Reported 4-18
by PWG
4-4 Effect of Formaldehyde Exposure on Cell 4-36
Proliferation in Level B of the Nasal
Passages
4-5 Effect of the Time of 3H-Thyroidine Pulse 4-37
on Cell Replication After HCHU Exposure to
Rat
4-6 Effect of HCHO Concentration vs. Cumulative 4-38
Exposure on Cell Turnover in Rats (Level B)
•
4-7 Effect of HCHO Concentration vs. Cumulative 4-38
Exposure on Cell Turnover in Rats (Level A)
4-8 Effect of HCHU Concentration vs. Cumulative 4-39
Exposure on Cell Turnover in Mice (Level A)
4-9 Frequency of Squamous Metaplasia in Level 2 4-42
of the Rat Nasal Cavity
4-10 Incidence of Lesions Other Than Tumors in 4-43
the Larnyx of Rats Exposed to Acetaldehyde
[Numeric]
4-11 Incidence of Epidermoid and Adenoid 4-43
. Squamous Carcinomas in Rats Exposed to
Hexamethylphosphor amide
4-12 Inhalation Carcinogenicity of Acetaldehyde 4-65
in Rats — Summary of Nasal Tumors
4-13 Summary of Studies Relevant to Formaldehyde 4-68
4-14 Power Calculations for SMR Studies 4-69
IV
-------
6.5. HCHO Levels in Homes and Garment
Manufacturing Sites 6-9
6.5.1. Manufactured Homes 6-9
6.5.2. Conventional Homes 6-18
6.5.3. Garment Worker Exposure 6-25
6.6. Summary 6-33
7. Estimates of Cancer Risk 7-1
7.1. Risk Estimates Based on
Squamous Cell Carcinoma Data 7-1
7.2. Risk Estimates Based on Polypoid
Adenoma Data 7-8
7.3. Uncertainty in Risk Estimates 7-10
7.4. Presentation of Risk Estimates 7-15
7.4.1. Separate Risk Estimates Derived
From Squamous Cell Carcinoma and
Polypoid Adenoma Data , 7-15
7.4.2. Calculate Risks Separately But
Add the Risks 7-18
7.4.3. Summary 7-22
8. Estimates of Noncancer Risks 8-1
8.1. Introduction 8-1
8.2. Studies Reviewed 8-1
8.3. Limitations of Studies 8-15
8.3.1, Study Design Limitations 8-15
8.3.2. Bias Limitations 8-16
8.4. Results 8-16
8.5. Discussion 8-20
9. Risk Characterization 9-1
9.1. Cancer 9-1
9.2. Other Effects 9-5
9.3. Summary 9-8
10. References 10-1
iii
-------
Table Title page
4
6-8 Frequency Distribution of Formaldehyde 6-24
Levels in Washington Conventional Non-
UFFI Homes
6-9 Pre-1980 Monitoring Data for Garment 6-27
Manufacturing and Closely Related
Industries
6-10 Recent Monitorign Data for Formaldehyde 6-28
in the Garment Manufacturing Industry
6-11 • NTOSH Monitoring Results - Ranges by 6-31
Department
6-12 Formaldehyde Concentration Levels 6-32
(ppm) - Garment Manufacturing
7-1 Estimated Individual and Population Risks 7-7
Based Upon Squamous Cell Carcinoma Data
From CUT Study. Population Risks (number
of excess tumors) Appear in Parentheses
Below Individual Risk Estimates
7-2 Risk Based on Polypoid Adenoma Data 7-9
8-1 Summary of Dose-Response Data for 8-2
Non-Carcinogenic Health Effects of
Formaldehyde
8-2 Summary of Selected Cross Sectional 8-9
Studies
8-3 Summary of Selected Controlled Human 8-13
Studies
8-4 Exposure Ranges for Selected Endpoints 8-23
9-1 Summary of Cancer and Noncancer Risks 9-9
VI
-------
Taole Title page
4-15 Conditional Power Calculations for PMR 4-70
Studies
4-16 Power Calculations for Case-Control Studies 4-71
5-1 Reported Health Effects of Formaldehyde 5-1
at Various Concentrations
5-2 Delayed Type Hypersensitivity (Human) 5-9
Due to Low Levels of Formaldehyde
5-3 • Significant Findings in Nasal Turbinates 5-12
in Rats
5-4 Significant Findings in Nasal Turbinates 5-12
in Monkeys
5-5 Total Incidence by Groups of Monkeys 5-12
6-1 Populations at Risk 6-5
6-2 Summary of Formaldehyde Concentrations 6-12
in Complaint Mobile Homes in Kentucky
from September 1979 Through December
1980
6-3 Potential Effects of Temperature and 6-15
Relative Humidity Changes on Formaldehyde
Air Concentrations
6-4 Frequency of Observations Found in 6-16
Concentration Intervals by Clayton
Environmental Consultants
6-5 Frequency of Observations Found in 6-17
Concentration Intervals by Wisconsin
Division of Health
(
<
6-6 Comparison of Non-UFFI Canadian Homes 6-20
by Average Formaldehyde Concentration
6-7 ORNL/CPSC Mean Formaldehyde Concentrations 6-22
(ppmf) as a Function of Age and Season
(Outdoor Means Are Less Than 25 ppb
Detection Limit)
-------
List of Figures
Figures Title page
4-1 Frequency of squamous metaplasia in the 4-4
nasal cavity of Fischer 344 rats exposed
to 2.0 ppm (top), 5.6 ppm (middle), or
14.3 ppm (bottom) of formaldehyde gas for
24 months. Nasal cavity Levels I, II, IV,
and V were not evaluated at the 6- and 12-
month interim sacrifices in the 14.3 ppm
exposure group.
4-2 Frequency of squamous metaplasia in the 4-6
nasal cavity of B6C3F} mice exposed to
14.3 ppm of formaldehyde gas.
4-3 Drawing indicating the level of sections 4-36
from the nasal passages of rats and mice.
4-4 simplified reaction sequence from drug 4-55
N-demethylation (cytochrome-P-450-dependent
monooxygenase) to HCHO, formate, and CO2
production (from Waydhas et al., 1978).
Reactions are: la, HCHO dehydrogenase (GSH);
ID, aldehyde dehydrogenase; Ic, catalase
(peroxidatic mode); 2a, 10-formyltetrahydro-
folate sythetase; 2b, 10-formyltetrahydro-
folate dehydrogenase; 2c, catalase
(peroxidatic mode).
4-5 Tetrahydrofolic acid pathway and 1-carbon 4-57
transfer for HCHO metaoolism.
4-6 overall metabolism of HCHO. 4-59
6-1 Levels of Mobile Homes Corresponding to 6-11
Year of Manufacture.
6-2 Frequency of Formaldehyde Levels, By 6-13
Home Age, Exceeding 1.0, 0.4, and 0.2
ppm In Clayton and Wisconsin Data
Combined.
6-3 Frequency Distribution of Levels in 6-26
Conventional Homes.
VII
-------
1. EXECUTIVE SUMMARY
Since 1979, when the preliminary results from the Chemical
Industry Institute of Toxicology (CUT) study indicated the
formation of nasal cancer in rats, much attention has been
focused on the potential human carcinogenicity of formaldehyde
(HCHO). However, it was HCHO's acute effects that initially
prompted the Federal government's effort to control HCHO
exposures from Urea-HCHO foam (UFFI) installations and high HCHO
emitting building materials in manufactured homes. Although
attention has shifted to the potential human carcinogenicity,
HCHO's other effects have the most immediate impact on persons
and continue to generate a substantial number of consumer
complaints. Consequently, this risk assessment will address
HCHO's carcinogenic and noncarcinogenic effects.
1.1. Carcinogenic Effects
Formaldehyde (HCHO) is carcinogenic by inhalation in males
and females of one strain of rat and in males of another strain,
and there is evidence of its carcinogenicity in mice. In the
CUT study (Kern et al., 1983), HCHO produced tumors of a type
with very low background rates after a short latency period and
with a dose-response relationship. The same malignant tumors
were also seen in the Albert Et al. (1982) and Tobe et al. (1985)
studies. Negative studies in other species, in this case the
hamster, do not reduce the weight given to the positive findings.
Other data support the bioassay data. HCHO's mutagenic
activity has been shown in a number of tests and it has been
1-1
-------
shown to be a weak promoter on mouse skin. HCHO has been shown
to be capable of eliciting benign tumors at concentrations which
fall within human exposure ranges and malignant tumors within an
order of magnitude above estimated human exposure. In addition,
other aldehydes which are structurally similar to HCHO, such as
acetaldehyde, malondialdehyde, and glycidaldehyde, have been
shown to have oncogenic potential* Finally? the existing
©pidemiologic data indicate that HCHO may be a human carcinogen.
The body of epidemioloyic data does not demonstrate that
HCHO is a human carcinogen because confounding due to exposure to
other substances cannot be eliminated; however, the studies do
suggest that HCHO may be a human carcinogen. Excess mortality
from leukeroias and brain cancers have been noted in a group of
professionals who use formalin. In addition, two case-control
studies show an association between nasal cancer and HCHO and
wood dust.
EPA has determined that, based on its proposed Cancer Risk
Assessment Guidelines, HCHO can be classified as a Group Bl-
Probable Human Carcinogen. This classification under the
Guidelines means that EPA has determined that there is limited
evidence of carcinogenicity to humans from epidemiologic studies
and sufficient evidence of carcinogenicity from animal studies.
1.2. Other Effects
Acute effects, irritation of the eyes and upper respiratory
system, are responsible for the majority of consumer complaints
about HCHO. Most persons experience discomfort within the range
1-2
-------
of 0.1 to 3 ppm HCHO. The eyes are generally the most
sensitive. For most persons odor recognition occurs at about 1
ppm HCHO and can be a marker for acute effects. More serious
effects occur at exposures above 3 ppm.
In addition to its sensory effect on receptors of the eyes,
nose, and throat, HCHO also causes inflammation and cellular and
tissue damage. Experiments in rats and aonkeys indicate that
chronic exposures over 1 ppm causes squamous metaplasia and
hyperplasia. Also, subchronic exposures of 2 ppn or greater
affect the mucociliary clearance system, causing mucostasis and
ciliastasis. Ultrastructural changes to cilia may be occurring
below 2 ppm. Possible impairment of the nasal mucociliary system
(and other mucociliary systems of tne respiratory system) by HCHO
has been linked to increased episodes of respiratory tract
infections in children.
A small number of reports associate HCHO with allergic
asthma-like symptoms. However, there are no sufficiently
well-controlled studies to establish whether HCHO is an inhalant
sensitizer.
On the other hand, HCHO is a well-known dermal sensitizer
and irritant. After sensitivity is induced, concentrations which
elicit allergic response range from as low as 30 ppm in a patch
test to 60 ppm HCHO from actual use of formalin. HCHO causes
allergic contact dermatitis (Type IV allergy) and probably
immunologic contact urticaria (hives or rash) (Type I allergy).
Nonallergic contact urticaria has also been reported from
multiple exposure.
1-3
-------
HCHO has been associated with a number of central nervous
system (CNS) disturbances such as memory loss, irritability, and
sleep disturbances. However, the human studies linking these CNS
effects to HCHO have many technical and design faults which make
the results questionable.
A limited number of reports have suggested that HCHO may
cause reproductive disorders,, However? no clear evidence exists
to link HCHO to adverse reproductive outcomes. In addition,
based on the available literature it is not likely that HCHO
poses a risk as a potential human teratogen.
1.3. Exposure
Two exposure categories are of primary concern: those
associated with manufacture of apparel from fabrics treated with
HCHO-based resins and those who reside in conventional and
manufactured homes containing construction materials in which
certain HCHO-based resins are used. Based on the monitoring data
available to EPA, the estimated exposure for apparel workers
ranges from 0.17-0.64 ppm. The estimated 10-year average
exposure to current manufactured home residents is approximately
0.20 ppm, while the 10-year average for manufactured homes under
the new Housing and Urban Development (HUD) Manufactured Home
Standard is 0.15 ppm. Exposures of conventional home residents
' ~.'' *••
•are lower* less than 0.1 ppm. However, this segment is not well
characterized, and exposures can be higher in new, energy
efficient homes.
1-4
-------
1.4. Risk Estimates
EPA estimates that there are approximately 800,000 apparel
workers, 4,200,000 manufactured home residents, and >100,000,000
conventional home residents exposed to HCHO.
Model-derived 95% upper confidence limits (UCL) and maximum
likelihood estimates (MLE) based on squamous cell carcinoma data
range from 1 X 10~3 [Bl] to 3 X 10~4 [Bl] at the UCL and 6 X 10~7
[Bl] to 4 X 10"9 [Bl] at the MLE for apparel workers, 2 X 10~4
[Bl] (UCL) and 1 X 10~9 iBl] (MLE) for manufactured home
residents (at the HUD standard), and a minimum of 3 X 10~4 [Bl]
(UCL) and 7 X 10"12 (MLE) for conventional home residents.
Associated maximum likelihood estimates are less than 1 X 10
for all catgories of concern. Risks based on polypoid adenoma
data are approximately an order of magnitude greater for the
exposures of concern.
Attempts to establish definitive dose-response relationships
for acute effects have not been successful. Techniques used by
the Occupational Safety and Health Administration (OSHA) and HUD
have some limited value in determining the percent responding at
any given HCHO exposure level. It appears that based on the
current human studies only broad response ranges can be
described. Consequently, for small differences in concentration,
say 0.4 to 0.8 ppm, it is not possible to determine the change in
response rates of a given exposed population. However, based on
animal data, the NOEL for cellular effects in the nasal cavity is
about 1 ppm. Because the mucociliary clearance system of the
1-5
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nasal cavity is an important bodily defense system, subchronic
exposures to HCHO greater than 1 ppm could be harmful. . The
margins of safety for the cellular and sensory effects at various
HCHO exposures were examined. At the OSHA standard of 3 ppm
there is no margin of safety. For garment workers small margins
of safety exist except for eye irritation. The situation is
:essentially the same for home residents.
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2. INTRODUCTION
In November 1979, EPA received information that the interim
results of a 24-month bioassay in rats conducted by CUT showed
that a number of the rats had developed nasal cancer after
inhalation of HCHO.
In November of 1980, the Federal Panel on Formaldehyde,
Corned by several Federal agencies under the aegis of the
National Toxicology Program, published a report finding that
CIIT's bioassay methodology was consistent with accepted testing
standards. Using the data available through the 18-month point
of the CUT study, the Federal Panel concluded that "formaldehyde
should be presumed to pose a risk of cancer to humans." Also in
November 1980, CUT presented the preliminary results of the full
study. CUT pathologists reported finding statistically
significant increases, as compared with controls, in the
incidence of malignant tumors in rats exposed to HCHO vapor at
the highest of the three levels they tested.
In February 1982, based on its evaluation of the toxicity
and exposure data on HCHO then available, EPA decided that,
although HCHO had been found to be carcinogenic under the
conditions of the test, the available information as to HCHO's
cancer risk to humans did not meet the statutory criteria for
priority designation under section 4(f) of TSCA.
To assist its evaluation of HCHO the Agency funded the
National Center for Toxicological Research to sponsor a Consensus
Workshop on Formaldehyde (the Workshop). The Workshop was held
2-1
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in Little Rock, Arkansas from October 3 through 6, 1983. Over 60
government, industry, university, and public interest
organization scientists served on the following eight Panels:
(1) Exposure; (2) Epidemiology; (3) Carcinogenicity/
Histopathology/Genotoxicity; (4) Immunology/Sensitization/
Irritation; (5) Structure Activity/Biochemistry/Metabolism;
{$) Reproduction/Teratology\ |7) Behavior/Heurotoxicity/
Psychological Effects; and (3} Risk Estimation* Each Panel
(except the Risk Estimation Panel) was charged with the task of
reviewing the major scientific studies relevant to that Panel's
area. Also, the Panel members were asked to address a number of
discussion topics and prepare a consensus report addressing those
topics.
When the Panel deliberations were finished, draft reports
were provided to the Risk Estimation Panel„ The Risk Estimation
Panel was charged with the task of determining how the data could
be integrated to make reasonable risk estimates for humans
exposed to HCHU at various levels and through different routes.
The decision process of the February 1982 decision under
section 4(f) of TSCA generated considerable controversy and
formed the basis for a lawsuit by the Natural Resources Defense
Cooncil .(SiRBCl and the American Public Health Association (APHA)
XNRDC v. Ruckelshaus, No. 83-2039, filed in the United States
District Court for the District of Columbia, July 18, 1983).
In view of public controversy concerning the process and
policy issues associated with the Agency's section 4(f) decision
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on the cancer hazard of HCHO, EPA announced in the FEDERAL
REGISTER of November 18, 1983 (48 FR 52507) its decision to
rescind its February 1982 decision, and to ask the public to
submit views, arguments, and data relevant to determining whether
HCHO should be given priority consideration under section 4(f) of
TSCA. Comments were due at EPA by January 17, 1984; EPA
announced that it expected to reach a new decision by May 18,
1984.
On May 23, 1984 EPA announced in the Federal Register (49 FR
21898) that two HCHO exposure categories triggered section 4(f)
of TSCA (possible widespread cancer risk). The exposures which
led to the decision are those associated with manufacture of
apparel from fabrics treated with HCHO-based resins and residence
in conventional and manufactured homes containing construction
materials in which certain HCHO-based resins are used. In
addition, EPA also published on the same day an Advance Notice of
Proposed Rulemaking (49 fR 21870) announcing the initiation of a
full investigation of regulatory options for the two categories.
In addition to HCHO's potential cancer risks, HCHO's other
effects should be considered in any action to reduce health
effects from HCHO. The assessment of the risks from acute
respiratory effects was prepared to be considered along with the
carcinogenic risk assessment in the overall investigation of
flCHO. The hazard discussion of noncarcinogenic effects in the
risk assessment is based in part on reports from the Consensus
Workshop on Formaldehyde, a report of the Cosmetic Ingredient
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Review Expert Panel, a hazard assessment by Ulsamer et al.
(1984), and the National Research Council report titled HCHO and
other Aldehydes prepared under contract to EPA. The risk
assessment focuses on the possibility of determining a dose-
response for these noncancer effects because while many of the
effects are well documented, the dose-response patterns in the
Jayraan population are not. Methods used by BUD and OSHA to relate
the proportion of the human population responding at particular
exposure levels have been analyzed. In addition, EPA -has
reviewed selected human studies to determine if dose-response
relationships can be described.
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3. PHYSICAL-CHEMICAL PROPRETIES
HCHO is the simplest member of the aldehyde chemical
category. It exists in many different forms. Pure monomeric
formaldehyde is a colorless, pungent gas at ordinary
temperatures. Aqueous formaldehyde, called formalin, is a clear,
colorless solution containing about 37 percent by weight of
dissolved formaldehyde in water, usually with 10 to 15 percent
nethanol added to prevent polymerization. The other forms of
formaldehyde are polymers, the best known of which are
paraformaldehyde and trioxane (trioxymethylene).
The molecular weight of HCHO is 30. It has the following
structural formula:
O
II
H-C-H
The chemical name used by Chemical Abstracts Service is
formaldehyde, and its Chemical Abstract number is 50-00-0.
Synonyms* include formaldehyd; formaldehyde gas; formaldehyde
solution; formalin; formalin 40; formalin 100%; formic aldehyde;
methaldehyde; methanal; methyl aldehyde; methylene glycol;
roethylene oxide; oxomethane; oxymethylene; paraform;
paraformaldehyde; polyoxymethylene glycols;
c( -polyoxymethylene; ^-polyoxymethylene; tetraoxymethylene;
C^-trioxane; trioxane; and ^C-trioxymethylene.
•Includes synonyms for polymeric forms of HCHO.
3-1
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The boiling and melting points for HCHO are -19°C and
-118°C, respectively. Vapor pressure is 400 mm at -33°C. HCHO
is soluble in water, acetone, benzene, diethyl ether, chloroform
and ethanol (IARC, 1982).
3-2
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4. HAZARD OP CARCINOGENIC EFFECTS
4.1 Long- and Short-Term Animal Tests
The first long-term study reporting the carcinogenicity of
HCHO in animals by the inhalation route was one by Kern et al.
(1983) (CIIT-sponsored study performed at Battelle Columbus
Laboratories) which reported statistically significant increased
levels of squamous cell carcinomas in the nasal cavities of rats
at 14.3 parts per million (ppm). In the study, groups of
approximately 120 male and 120 female Fischer 344 strain rats and
C57BL/6 X C3HFj strain mice, were exposed by inhalation to 0,
2.0, 5.6, or 14.3 ppm of HCHO gas for 6 hours per day, 5 days per
week, for 24 months. Sguamous cell carcinomas were observed in
the nasal cavities of 103 rats (52 females and 51 males) and 2
male mice exposed to 14.3 ppm of HCHO and in 2 rats (one male and
one female) exposed to 5.6 ppm of HCHO gas. The incidence of
nasal carcinomas in rats showed a dose-response relationship.
See Table 4-1 for a summary of tumor response in rats.
Although the two squamous carcinomas in mice at 14 ppm were
not considered by the investigators to be statistically
significant in comparison with the incidence in control mice in
the study, the finding suggests that the effect is related to
HCHO exposure because the natural background rate for such nasal
cancers is very low in this strain of mice, with only one
neuroepithelioraa and one angiosarcoma having been reported by
Stewart et al., 1979 (Kern et al., 1983).
4-1
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**!• 4-1.
m me wea*. oormr
-------
The difference in susceptioility of rats and race may be
due, in part, to a greater reduction in respiratory minute volume
in mice than in rats during exposure to an irritating agent. In
a study by Chang et al. (1983) changes in minute volume, nasal
cavity disposition, and cell proliferation were examined. It was
found that mice exposed to 15 ppm HCHO for 6 hours experienced an
approximately 50% reduction in minute volume. If a "dose", of
HCHO is calculated from adjusting for reduction in minute volume
and other data, it can be seen that for mice the dose received at
14.3 ppm in the Kern et al. (1983) study is one-half that
received by rats at 14.3 ppm (see also Swenberg et al., 1983).
Thus, the tumor response in mice at 14.3 ppm is comparable to the
response in rats at 5.6 ppm. Interestingly, mice and rats at
these exposures showed nearly identical tumor responses, i.e.,
two squamous cell carcinomas out of approximately 240 mice and
rats.
In addition to the squamous cell carcinomas, small numbers
of benign tumors characterized as polypoid adenomas were observed
in rats at each dose level. These benign tumors did not exhibit
a dose-response relationship. However, because this type of
benign nasal tumor is rare in control rats it is likely related
to HCHO exposure. For a further discussion of these lesions and
their use in this risk assessment see Data Selection for
Quantitative Analysis after this section.
Significant non-neoplastic lesions were also observed. See
Figure 4-1 for type, severity, and locations. In rats at 2.0
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Figure 4-1. Frequency of sguasaows metaplasia in the nasal
cavity of Fischer 344 Eats exposed to 2.0 ppm (top), 5.6
ppm (middle), or 14.3 ppm (bottom) of formaldehyde gas for
24 months. Nasal cavity Levels I, II, IV, and v were not
evaluated at the 6- and 12-month interim sacrifices in the
14.3 ppm exposure group. Figure taken from Kern et al.
(1983).
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ppiri, purulent rhinitis, epitneiial dysplasia, and
metaplasia were present in the anterior portion of the turbinates
(Level I) at 12 months. The frequency of metaplasia increased up
to 24 months and then decreased at 27 months (three months post
exposure). In the 5.6 ppm group, purulent rhinitis/ epithelial
dysplasia, and squamous metaplasia were observed in the anterior
and middle portions of the nasal cavity (Levels I, II, and
III). Regression of squamous metaplasia was noted at 27
months. Similar lesions were observed in the 14.3 ppm exposure
group in all regions of the nasal cavity. Regression of squamous
metaplasia was only observed in the posterior portion of the
nasal cavity (Levels IV and V).
Inflammatory, dysplastic, and squamous metaplastic
alterations of the respiratory epithelium of mice were
observed. These lesions were most severe in the 14.3 ppm
exposure group (see Figure 4-2). A few mice in the 5.6 ppm group
had dysplastic changes at 18 months. At 24 months, there were
only a few mice with dysplasia, metaplasia, or serous rhinitis.
Mice in the 2.0 ppm group were generally free of significnat
lesions with only a few animals with serous rhinitis at 24
months.
One complication noticed during the Kern et al. (1983) study
was a spontaneous outbreak in rats of sialodacryeoadenitis. The
evidence for this consisted of (a) decreased body weight in all
dosed and control rat groups at about the 52nd week of the
experiment, followed by prompt recovery of body weight; and (b)
histopathologic demonstration of typical lesions in lacrimal and
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\
100
•0
40
w
016 Montr*
• MMorew
D 27 Montr*
Figure 4-2. Frequency of squamous metaplasia in the nasal
cavity of B6C3Fj mice exposed to 14.3 ppm of formaldehyde
gas. Figure taken from Kern et al. (1983).
salivary glands of dosed and control rats in the 12-month
sacrifice groups. Evidence of sialodacryeoadenitis was not found
in rats sacrificed at 6 or 13 months or in those with unscheduled
deaths. Virus isolation? viral antigen demonstration, and
serolo^ic tests for antibodies were not attempted in rats or
mice.
With regard to HCHO in the exposure chamber, a panel of
experts reviewed the method of generation of HCHO and monitoring
and agreed that "the Battelle approach to HCHO vapor generation
was a suitable adaptation of accepted methods and principles and,
.-/therefore, was sound and based upon the best available
technology. The same type of assessment applied to the chamber
air monitoring system, which also combined two well established
procedures" (Gralla et al., 1980).
4-6
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Other studies support the results of the Kern (CUT)
study. In two studies reported by Albert et al. (1982> (complete
results for one study and preliminary results for the other),
rats were exposed for life by inhalation to HCHO alone, mixtures
of hydrochloric acid (HCL) and HCHO, or HCL alone.
In the first study, 99 male rats were exposed to a mixture
of HC1 and HCHO (premixed at high concentrations before
introduction into the exposure chamber to maximize the production
of bis(chloromethyl) ether (BCME)). This was done because the
investigators were studying the hazard associated with the use of
HC1 and HCHO in close proximity in the workplace. A report had
suggested the production of BCME from mixing HCL and HCHO yas.
The average concentrations were 10.6 ppm HCL, 14.7 ppm HCHO, and
about 1 part per billion (ppb) BCME. Of the 99 animals exposed
to the test mixture, 25 developed sguamous cell carcinomas of the
nose. The contribution by the BCME was thought to be minimal
because the expected response to 1 ppb of BCME was estimated to
be less than 1.5 percent and there was a 25 percent incidence of
nasal tumors in the study. In addition, BCME normally produces
neurogenic carcinomas (mainly esthesioneuroepitheliomas), none of
which were seen in the study.
The second Albert et al. (1982) study, in which male rats
(100 per group) were exposed to HCL alone (10.2 ppm), premixed
HCL-HCHO mixture (14.3 ppm HCHO/10.0 ppm HCL), nonpremixed HCHO-
HCL mixture (14.1 ppm HCHO/9.5 ppm HCL), or HCHO alone (14.2
ppm), showed statistically significant numbers of squamous cell
4-7
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carcinomas of the nasal cavity in the rats exposed to HCHO alone
and the HCL-HCHO mixtures. A control group of 100 rats was
used. No nasal cancers were seen in the HCL-only exposed rats or
in the controls. Also, it appeared that the irritant HCL gas did
not enhance the carcinogenic response of HCHO because the
frequency of tumors was similar in the HCHO alone and HCHO-HCL
groups. Table 4-2 displays final results as reported to OSHA by
Albert (see OSBJW 1984),
In a study reported by Tobe et al. (1985), groups of 32 male
Fischer 344 rats were exposed to HCHO for 6 hours per day, 5 days
per week, for 28 months. The five test groups were as follows:
colony control, room control, 0.3, 2.0, and 15 ppm HCHO. The
significant finding was squaraous cell carcinoma (14 cases) and
papilloma (5 cases) in the 15.0 ppm group. No tumors were
observed in the Q»3 and 2=0 ppra groups. Rhinitis, squamous
metaplasia and hyperplasia of the nasal respiratory epithelium
were observed in all HCHO exposed groups.
It should be noted that while the carcinoma response was
similar between the Kern, Albert and Tobe studies, the benign
tumor response was markedly different. In the Kern study only
benign polypoid adenomas were observed, whereas in the Albert and
Tobe studiesbenign paplllemas were observed. The basis for
^tiese differences is difficult to explain, it could represent a
strain difference or some unknown factor. (Tobe used the same
strain of rats as Kern, Fischer 344, but the small number used at
each dose as-compared to Kern (32 vs. 240) may explain the
4-8
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Itfbl* 4-2.
i
10
SUMMV -prenixod 14 ppn
HCHO 6 10 \vpm HCL
(100 rats)
27
10
0
2
0
1
*0ata From G6HA (1984)
-------
failure of polypoid adenomas to be detected.) Consequently,
statements about the significance of these lesions in discussions
of human risk must be approached witn caution.
Two other chronic inhalation studies with HCHO designed to
investigate possible cocarcinogenic effects of this agent in the
upper and lower airways have been reported (Horton et al., 1963,
and Dalbey et al.? 1982}» Since the nasal tissues were not
systematically examined histologically, the value of these
studies in assessing the carcinogenicity of HCHO is accordingly
limited. In spite of these reservations, the studies have some
bearing on HCHO carcinogenicity.
In the study reported by Horton et al. (1963), C3H mice were
exposed to coal tar aerosol and/or to HCHO at concentrations of
40, 80, 160 ppm. Exposures were carried out for 1 hr/day, 3
days/week for 35 weeks, except for the 160 ppm group which was
exposed only for 4 weeks because of toxicity. Only 15 mice
survived to 1 year. There is no mention of histopathological
evaluation of nasal tissues, so presumably no grossly visible
tumors were observed. Coal tar aerosol exposure resulted in lung
tumor formation in 5 animals (1 invasive carcinoma), but HCHO
Vexposure did not. No evidence was found for any cocarcinogenic
effects of HCHO. The major shortcomings of this study for
*ej»valuafcing the carcinogenicity of HCHO are that too few animals
survived past one year* the individual exposures were short, most
groups were exposed only for 35 weeks, and histopathology was
inadequately reported.
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In a study by Daloey et al. (1982) male Syrian golden
hamsters were used to study the chronic effect of HCHO and
diethylnitrosamine (DEN). In the first part of the study, 88
hamsters were exposed to 10 ppm HCHO, 5 times/week for
lifetime. There were 132 untreated controls. The second part of
the study examined HCHO's promotional potential. For the second
part of the study the hamsters were divided into 5 groups: 50
untreated controls; 50 hamsters exposed to 30 ppm HCHO, 5
hrs/day, 1 day/week for life; and 3 groups receiving DEN
injections of DEN (0.5 mg, once per week for 10 weeks). Of the
three groups receiving DEN, one consisted of 100 hamsters
receiving only DEN, a second group of 50 hamsters were exposed to
50 ppm (5 hrs) of HCHO 48 hours prior to each injection of DEN,
and the third group was exposed to 30 ppm HCHO (5 hrs/day, 5
days/week) for life, beginning 2 weeks after the last DEN
injection.
In the hamsters exposed to 10 ppm HCHO for life there was no
evidence of carcinogenic activity. Toxic effects of HCHO in the
nasal cavity were limited to hyperplastic and metaplastic areas
in 5% of the hamsters. No hyperplasia or metaplasia was observed
in the controls. The incidence of rhinitis was similar in both
control and exposed hamsters, and was not considered to be
related to exposure of HCHO.
Caution must be exercised when comparing this part of the
Oalbey et al. (1982) study with the Kern et al. (1983) study.
One factor that should be considered is that the pathological
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evaluation in the Dalbey et al. (1982) study was less rigorous.
Only 2 sections of the nasal turbinates were examined as compared
to sections taken from 5 anatomical levels of the nasal cavity of
rats in the Kern et al. (1983) study.
Also, the Kern et al. (1983) study used three HCHO exposure
levels ( 2.0, 5.6, and 14.3 ppra) whereas only 10 ppm of HCHO was
used in the Dalbey et ale (1982) study„ If one compares the ppm-
i*?3/&d@k received by rats at 5.6 ppm in"the Kern study and hamsters
at 10 ppm, one sees that the ppro-hrs/week for the hamster is
equivalent to a hypothetical dosing regimen of 8.3 ppm for rats
(5.6 ppm X 6 hr/days X 5 days = 168 ppm-hrs/week vs. 10 ppm X
5 hr/days X 5 days » 250 ppm-hrs/week; this is equivalent to
250 ppm-hrs «
6h/d X 5d/wk 250 ppm-hrs/wk 4 6 hr/day X 5 d/wk =8.3 ppm).
Since only two squamous cell carcinomas were seen in the Kern et
al, (1983) study out of 240 rats at 5.6 ppm, the likelihood of
detecting a tumor in the Dalbey et al. (1983) study, which used
88 hamsters, is poor. In fact, there is a 30% probability that
the absence of tumors is due to chance.
Finally, it is well established (Kane et al., 1979 and
Buckley et al., 1984) that many sensory irritants decrease the
respiratory rate of exposed animals. For rats the RD50
(concentration required to reduce respiratory rate by 50%) is
approximately 32 ppm and for mice it is 3.1 ppm. if one assumes
that the sensory irritant response is found in hamsters (little
data have been developed on the hamster in this regard) (see
Alarie, 1985), it is possible that the hamsters in the Dalbey et
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al. (1982) study reduced their respiratory rate at the 10 ppm
level by some percentage, say 20 percent. This would be the
equivalent of a hypothetical exposure of 6.6 ppm in the Kern et
al. (1983) study which would further lessen the chance of
detecting a tumor response.
Although an RD50 value has not been reported for hamsters, a
study by Feron et al. (1978) comparing the responses of hamsters,
rats, and rabbits to acrolein vapor indicates that hamsters nay
resemble mice more in their respiratory response to HCHO than
rats. The hamsters were slightly affected (nasal cavity lesions)
at 1.4 ppm and severely affectd at 4.9 ppm by the acrolein. In
contrast, rats were slightly affected at 0.4 ppm and were more
severely affected at 1.4 and 4.9 ppm. This response is similar
to the difference in response (nonneoplastic lesions) between
rats and mice in the Kern et al. (1983) study where rats were
affected at all dose levels whereas mice, because of a lower RD50
value for HCHO, were affected only slightly at 5.6 ppm and more
seriously at 14.3 ppm. Since the mouse RDSO's for acrolein and
HCHO are 1.7 ppm and 3.13 ppm respectively (Kane et al., 1977),
which indicates that acrolein is a more potent sensory irritant,
one would expect that rats would experience more severe lesions
fron acrolein at exposure levels below those of HCHO that evoked
•responses in the Kern et al. (1983) study. This is in fact the
case. In a study by Rusch et al. (1983), rats were unaffected at
1.0 ppm HCHO, whereas in the Feron et al. (1978) study rats were
affected at 0.4 ppm (acrolein). Thus, it seems, plausible that
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hamsters are more like mice in their response to certain sensory
irritants.
In the second part of the Dalbey et al. (1982) study no
tumors were observed in untreated hamsters or those hamsters
receiving only HCHO. However, 77% of the DEN-treated controls
had a tumor (adenomas) at ten or more sites in the respiratory
tract. Although HCHO exposure concurrent with or after DEN
treatment did not increase the number of tumor-bearing animals
(TBA), the number of tumors/TBA (tracheal tumors) was nearly
doubled over DEN-only controls when HCHO was administered
concurrently with DEN treatment, whereas post-HCHO treatment had
no measurable effect. Thus, under conditions of the test, HCHO
appears to be able to act as a cofactor in chemical
carcinogenesis. However, there was a corresponding decrease in
lung tumors in hamsters exposed to both agents, this suggests
that the effect on the trachea may be within the limits of
experimental variability (Consensus Workshop on Formaldehyde,
1984).
In a study by Rusch et al. (1983) groups of 6 male
Cynamologus monkeys, 20 male and 20 female Fischer 344 rats, and
10 male and 10 female Syrian golden hamsters were exposed to 0,
0.20» 1.0 and 3.0 ppm HCHO for 22 hrs/day, 7 days/week, for 26
*week»e 3he most significant finding was squamous metaplasia/
hyperplasia in rats and monkeys at 3.0 ppm, little or no response
was seen at the lower exposure levels. Hamsters did not show any
significant responses at any exposure level. The results from
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this study indicate that concentration may be more important than
total dose if squaraous metaplasia/hyperplasia is the response
measured when the results are compared to those of the Kern et
al. study. In the Kern study squaraous metaplasia was found in
rats in the 2.0 ppm exposure group during the course of the
exposure (2.0 ppm 6 hr/day, 7 days/week, for life). However, in
the Rusch et al. (1983) study rats exposed to 1.0 ppm HCHO had no
squamous metaplasia even though they received a total dose 2.5
times that received by the rats at 2.0 ppm in the Kern et al.
(1983) study. However, this study was inadequate to show a
neoplastic response because of the small number of animals and
its short duration.
The carcinogenicity of HCHO also has been tested by a
variety of other routes of administration including subcutaneous
injection in rats (Watanabe et al. 1954, 1955), ingestion by mice
and rats (Delia Porta et al. 1968, 1970), and application to the
buccal mucosa in rabbits (Meuller et al., 1978). Because of
shortcomings in experimental protocols, none of these studies
permits firm conclusions regarding HCHO carcinogenicity.
Nonetheless, some of the studies give definite clues that HCHO
nay be carcinogenic to a variety of target tissues as well as to
a variety of animal species (and not only to the nasal epithelium
of rats).
The most revealing study in this regard is that by Meuller
et al. (1978) who applied a solution of 3% formalin to the oral
mucosa of rabbits, using an "oral tank." Each exposure lasted
4-15
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for 9tf minutes and was repeated 5 times per week for a .period of
10 months. As a result, 2 out of 6 rabbits developed grossly
visible leukoplakias that, according to the authors, showed
histological features of carcinoma in situ. Unfortunately, the
Information given on the histomorphology of the lesions is very
•canty.
Other experiments which suggest that HCHO produces
eareinogenic effsets are those £>y Matanabe et al. (1954, 1955),
who injected rats (strain unknown) subcutaneously with formalin
and with hexamethylenetetramine (HMT, from which HCHO is
liberated in vivo).
However, several other studies carried out with HMT by
Brendel (1964) who administered HMT by gavage to rats and Delia
Porta et al. (1968, 1970) who administered HMT in drinking water
to mice and rats, resulted in negative findings. The
significance of these finding must be tempered by the fact that
chemicals often give disparate results by different routes of
exposure. For example, hexamethylphosphoramide (HMPA) is a
potent nasal carcinogen by inhalation, but was not carcinogenic
in rats fed HMPA for 2 years (Lee et al. , 1984).
A study by Klenitzky (1940) in which "formol oil" was
applied SO times to the cervix uteri of mice resulted in no
tumors.
Finally, a study by Spangler et al. (1983) has been
interpreted as showing weak promoting activity of HCHO on mouse
skin. However, in another study by Krivanek et al. (1983) no
4-16
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promotion was observed when nonirritating applications of HCHO
were used (Consensus Workshop on Formaldehyde, 1984).
4.2. Data Selection for Quantitative Analysis
As discussed above, there are a number of studies available
which indicate the carcinogenic potential of HCHO. For the
purpose of Quantitative Risk Assessment, the Agency generally
chooses a well-designed and conducted study that uses the most
sensitive species of animal.
In the case of HCHO, only one nultidose, long-term study is
available, the Kern et al. (1983) study (CUT study). This study
has been reviewed by a number of panels (IRMC, 1984; Consensus
Workshop on Formaldehyde, 1984) and has been found to be of
sufficient quality for risk estimation purposes. The selection
of the Kern et al. (1983) is consistent with EPA's proposed
Carcinogen Risk Assessment Guidelines (EPA, 1984a). Since
squamous cell carcinomas were the only statistically significant
malignant tumors observed in the study, they will be used for
quantitative risk assessment. A small number of benign tumors,
were also observed. The Guidelines state that benign tumors
should be combined with malignant tumors for risk estimation
unless the benign tumors are not considered to have the potential
to progress to the associated malignancies. The following
discusion explores this question.
4.2.1. Polypoid Adenomas/Other Tumors Observed
In the Kern et al. (1983) study, a small number of polypoid
adenomas were reported in the rats: 1, 8, 6, and 5 adenomas in
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the 0, 2.0, 5.6, and 14.3 ppm groups, respectively. Because a
number of questions were raised about the accuracy of the
diagnosis of these lesions, they were reexamined by a pathology
working group (PWG) (Boorman, 1984; Consensus Workshop, 1984).
The results of the PWG reexamination are as follows: 1, 8, 5,
and 2 adenomas in the 0, 2.0, 5.6, and 14.3 ppm groups,
respectively. However, two adenomas diagnosed at 2.0 ppm and one
at 5.6 ppm were borderline calls between focal hyperplasia and
small benign tumors. See Table 4-3 for a breakdown by dose and
sex. In addition, two lesions originally diagnosed as nasal
carcinomas were rediagnosed as adenocarcinoma and poorly
differentiated carcinoma which were thought to be morphologically
related. This has relevance to the following discussion of the
potential of polypoid adenomas to progress to a cancer.
Table 4-3.
INCIDENCE OP POLYPOID ADENOMA AS
REPORTED BY PWG
Sex
M
Nasal cavities
evaluated***
Nasal cavities
::- evaluated
Combined
Nasal cavities
evaluated
DOSE (ppm)
0
1
(118)
0
(114)
1
(232)
2.0
4*
(118)
4
U18)
8
(236)
5.6
5**
(119)
0
(116)
5
(235)
14.3
2
(117)
0
(115)
2
(232)
Statistically
Total Signifleant"
12 No
No
16 Yes at 2.0 ppm
*One tailed Fisher exact test.
*Two tumors in-this group were judged to be borderline
lesions between small benign tumor and focal hyperplasia.
**One tumor in this group was judged to be a borderline
lesion between small benign tumor and focal hyperplasia.
***From Kern et al. 1983.
4-18
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The PWG was asked to speculatea about the possible
progression-of the polypoid adenomas. The consensus of the PWG
was that there was no evidence that polypoid adenomas progressed
to equamous cell carcinomas and that they should not be combined
with squamous cell carcinomas for statistical purposes (Boorman,
1984)* This recommendation was accepted by the Risk Estimation
Panel of the Consensus Workshop on Formaldehyde (1984). However,
a small number of other cancers were seen in the Kern et al.
(1983) study. These included one adenocarcinoma, one poorly
differentiated carcinoma, one carcinosarcoma, and two poorly
differentiated carcinoma/sarcoma. The Carcinogenicity/
Histopathology/Genotoxicity Panel of the Consensus Workshop on
Formaldehyde (1984) stated that "[T)he polypoid adenomas can be
evaluated separately and in combination with the nonsquamous
carcinomas that were observed in the 14 ppm rats." It is
possible that one of these lesions may represent the malignant
counterpart of polypoid adenoma. However, the nature and
progression of benign nasal tumors is not well understood.
Studies by Lee et al. (1984), Takano et al (1982), and
Reznik et al. (1980) have examined the morphology of nasal tumors
in rats caused by exposure to hexamethylphosphoramide (HMPA),
1,4-dinitrospiperazine, and l,2-dibromo-3-chloropropane,
respectively. In the Reznik et al. (1980) study, 78% of the
tumors in males and 66% in females in the low dose group were
benign (adenomas and squamous-cell papillomas). However, in the
high dose group 89% and 76% of the tumors in males and females,
4-19
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respectively, were malignant (adenocarcinomas and squamous-cell
carcinomas). It does not appear that the shift from primarily
benign tumors at the low dose to primarily malignant tutors at
the high dose means that the benign tumors were progressing to
their malignant counterparts. Most of the benign tumors were
located in the anterior part of the nasal cavity, while most of
the malignant, tumors were located in the region of the
ethmoturbinates and the posterior part of the nasal septum.
Adenomas and adenocarcinomas were often seen in rats at the same
time and dose, but in different parts of the nasal cavity.
In the Takano et al. (1982) study, 5 different proliferative
lesions were seen: simple hyperplasia, papillary hyperplasia,
nodular hyperplasia, papilloraa, and carcinoma (mostly
adenocarcinomas). Papillary hyperplasia and papilloma were
mainly located in the anterior regions of the nasal cavity.
Modular hyperplasia and adenocarcinoraa, on the other hand, were
found in the posterior regions. Also, these pairs of lesions
often coexisted in their respective locations. The conclusion of
the authors was that papillary hyperplasia progresses to
papilloma and that nodular hyperplasia progesses to
adenocarcinoma.
The studies by Lee at al. (1982, 1984) showed that HMPA
e«w»«d-«ainly epidermoid (squamous cell) carcinomas (71%),
-adenoid squamous carcinoma (15%) and squamous cell papilloma .
<8.2%). (A small number of adenomatous polyps were seen with
adenoid squamous carcinomas.) The squamous cell papillomas were
4-20
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mostly exophytic, which may indicate that they may not represent
the benign^counterpart of the epidermoid carcinomas for two
reasons. First, in the Takano et al. (1982) study, nodular
hyperplasias rather than papillomas seemed to progress to
adenocarcinomas. Second, the papillomas and nodular hyperplasias
are similar to human exophytic and inverted papillomas/
respectively. In humans, carcinomas apparently arise from
inverted papillomas rather than exophytic papillomas.
The experience with other chemicals (see Lee et al., 1982)
and the foregoing illustrate the variability of the types and
locations of the tumors found. In addition, except in limited
cases, the progression of preneoplastic and benign neoplasms to
malignant neoplasms is not known with any assurance. Also,
although some studies of chemicals show a tumor profile that is
predominantly benign at low doses and malignant at high doses
(NTP, 1962a; NTP, 1962b) other studies, such as of HMPA, show
primarily malignant tumors at all dose levels eliciting a
response. This may be the result of a speed-up of the
carcinogenic process at higher doses in the former case or as in
the latter one the chemical may be so potent that even at low
doses progression is completed before termination of the study.
Zn the Kern et al. (1983) study, two main types of tumors
were seen: polypoid adenomas and squamous cell carcinomas. In
discussing these two lesions the Consensus Workshop on
Formaldehyde (1984) recommended that they not be combined "for
risk estimation because of differences in the cell type of
4-21
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origin." However, the Conference did recommend that they be
evaluated separately and in combination with the nonsquamous
carcinomas. Since an adenocarcinoma and a morphologically
similar carcinoma were seen in the study, the polypoid adenomas
nay represent the benign counterpart of these lesions. However,
the PWG stated that these lesions might arise de novo, originate
from cubmucosal glands, arise in polypoid adenomas, or a
eeiabination of the above» Also, the PWG stated that "not enough
information was available about nasal cavity tumors to predict
the possibility of benign tumors progressing to carcinomas." As
for the possibility that the polypoid adenomas may be the benign
counterpart of carcinosarcomas, this seems unlikely due to
different tissue type. Added to this are the lack of dose-
response, diagnostic uncertainties (3 of the 12 tumors were
borderline calls), and the poor statistical significance of these
lesions.
Finally, as discussed earlier, in the Albert et al. (1982)
and the Tobe et al. (1985) studies papillomas rather than
polypoid adenomas were observed and in the Kern et al. (1983)
study only polypoid adenomas were observed. This intraspecies
(and intrastrain since Tobe et al. and Kern et al. used Fischer
344 rats) difference also adds weight to the uncertainty in using
the polypoid adenoma data for risk estimation purposes. Whether
-the difference in benign tumors observed is due to a strain
difference is not clear. However, the separate appearance of two
distinct types of benign tumors further calls into question the
4-22
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significance of these lesions regarding their aDility to progress
to squaroous-cell carcinomas and their relevance in estimating
human risk.
Consequently, because there are so many uncertainties
associated with the polypoid adenoma data, it is recommended that
(1) they not be combined with squamous cell carcinomas (pooling)
for statistical purposes/ and (2) risk estimates should be
generated separately using the polypoid adenoma data (see
Sections 7.2 and 7.4).
4.3. Short-Term Tests; Mutagenicity/Genotoxicity
HCHO has been shown to produce mutations in a wide range of
test systems. Mutagenic activity of HCHO has been demonstrated
in viruses, Escherichia coli, Psendomonas pluonescens, Salmonella
typhimurium, and certain strains of yeast, fungi, Drosophila,
grasshopper, and mammalian cells (Ulsamer et al., 1984). HCHO's
ability to cause single strand breaks in DNA, DNA-protein cross-
links, sister chromatid exhanges (SCO, and chromosome
aberrations has been demonstrated (Consensus Workshop on
Formaldehyde, 1984).
In vitro studies have shown HCHO's ability to transform
BALB/c 3T3 mouse cells, BHK 21 hamster cells, and C2H-10T1/2
mouse cells and to enhance the transformation of Syrian hamster
embryo cells by SA7 adenovirus, and to inhibit DNA repair
(Consensus workshop on Formaldehyde, 1984). HCHO also causes
increases in the frequencies of observed mutations in the
presence of other mutagens, such as X-rays, ultraviolet
4-23
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radiation, and hydrogen peroxide. Compared to strains of E. coli
and Saccharomyces cerevisiae with normal repair mechanisms, HCHO
caused greater lethal and mutagenic effects in excision repair-
deficient strains (Ulsamer et al., 1984).
In reviewing much of the above literature, the Consensus
Workshop on Formaldehyde (1984) "found that the recent work is
eaore likely to find HCHO a mutagen than earlier studies, and is
also more likely to show a dose-response relationship. These
results are most probably attributable to the greater
sophistication in the way the later assays were carried out. It
should be noted that in the above studies, the relationship
between the cytotoxicity induced by HCHO and mutagenicity or
transformation induced by this agent is typical of most mutagens/
carcinogens that are positive in these assays. The data we have
reviewed are consistent with HCHO acting as a weak mutagen (i.e.,
less than a ten-fold increase over background)."
In a study by Grafstrom et al. (1983) using cultured
bronchial epithelial and fibroblastic cells, HCHO's ability to
•
cause the formation of cross-links between DNA and proteins,
cause single-strand breaks in DNA, and inhibit the resealing of
•ingle-strand breaks produced by ionizing radiation has been
shown, HCHO also inhibited the unscheduled DNA synthesis that
occurs after exposure to ultraviolet irradiation or to benzo-
lajpyrene diolexepoxide, but at doses substantially higher than
those required to inhibit the resealing of x-ray induced single-
strand breaks.'
4-24
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As a follow-up to the above study, Grafstrom et al. (1954)
investigated the repair of DNA damage caused by HCHO in human
bronchial epithelial cells and fioroblasts, skin fibroblasts, and
DNA excision repair-deficient skin fibroblasts from donors with
exeroderma pigmentosum. Exposure of these cell types to HCHO
caused similar levels of DNA-protein cross-links (DPC) and DPC
removal in all cell types. The half-life for DPC's was about 2-3
hours. An examination of the induction and repair of DNA single-
strand breaks (SSB) showed that the production of SSB was dose
dependent, and that the removal of SSB occurred at rates similar
to the removal of DPC. In addition, the results indicate that
exposure to HCHO causes SSB without the involvement of excision
repair, and that excision repair of HCHO damage may increase the
SSB frequency. HCHO also enhanced cytotoxicity of ionizing
radiation and N-methyl-n-nitrosaourea in normal bronchial
epithelial cells and fibroblasts. The authors speculated that
the inhibition of DNA-repair probably involves the interaction of
HCHO with cellular proteins of importance in DNA repair. They
noted that the repair of DNA lesions caused by ultraviolet
radiation has been shown to be inhibited by alkylating agents.
In a related study, Grafstrom et al. (1985) investigated the
effect of HCHO on the repair of O6-methylguanine and the ability
of HCHO to potentiate the mutagenicity of N-methyl-N-nitrosourea
(NMU) in normal human fibroblasts. When rate of DNA repair was
measured for NMU-treated cells that were incubated with HCHO, a
significantly lower rate of DNA repair was observed compared to
4-25
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NMU-treated cells. The authors proposed that HCHO inhibits DNA
repair by binding to the active site of O6-alkylguanine DNA
alkyltransferase. Also, although NMU and HCHO are weak mutagens,
addition of HCHO to NMU-treated cells resulted in a significantly
higher nutation frequency than was found with HCHO or NMU
alone. The increase may be due to HCHO inhibiting O6-methyl-
Qusnine repair CGrafstrom et al.* 1985).
& recent study by Casanova°schmitz et al» (1984) has
reported the difference between metabolic incorporation and
covalent binding in the labelling of macromolecules in rat nasal
mucosa and bone marrow by inhaled [14CJ- and [3H] HCHO. Rats
were exposed to labelled HCHO at concentrations of 0.3, 2, 6, 10,
or 15 ppm for 6 hrs, one day following a single pre-exposure to
the same concentration of unlabelled HCHO. The principal finding
reported by the authors was the apparent nonlinearity in the
amount of covalent binding of HCHO to DNA of the respiratory
mucosa. The amount of HCHO covalently bound to mucosal DNA at 6
ppm was reported to be 10.5 times higher that at 2 ppm, whereas
covalent binding to protein increased in a linear manner with
increases in HCHO concentration. No covalent binding was noted
in tissues from the olfactory mucosa or bone marrow. The
apparent nonlinear covalent binding of DNA between 2 and 6 ppm
%as been used as an input in quantitative estimation of risk from
HCHO exposure (Starr et al., 1984).
" The interpretation of the results from the Casanova-Schmitz
et al. (1984) study have been intensively reviewed (Cohn et al.,
1985) The principal conclusions of the reviewers are as follows:
4-26
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1. The implication that the number of DNA-protein cross-
links is important to risk assessment must be viewed in
light of the facts that the mechanism of formaldehyde
carcinogenesis is presently unknown, and that
formaldehyde may contribute to carcinogenesis in more
ways than directly damaging the genome (Cohn, 1984).
The relationship between DNA-protein cross-links and
carcinogenesis has not been defined for formaldehyde or
other chemical carcinogens.
2. The assertion that the measurement made "is a direct
measure of the dose of formaldehyde that reacts with
DNA" requires proof that the parameter measures the
result of all agent reactions with DNA, including DNA
adducts, reactions with cellular nucleic acids (Beland
et al., 1984; Feldman, 1975; Wilkins and MacLeod, 1976),
and possible DNA small molecule cross-links, etc.
Approximately 80% of DNA-protein cross-links are
eliminated in one hour (Wilkins and McLeod, 1976), a
fairly rapid repair which may not be characteristic of
all formaldehyde DNA damage, such as stable DNA-
formaldehyde adducts (Beland et al., 1984). Also, there
is no reason to expect that short-term exposure is
representative of chronic exposure. In fact, there is
evidence to the contrary since cell proliferation
decreases after 9 days (Swenberg et al., 1983), and
squamous cells eventually replace respiratory epithelial
cells (CUT, 1981), processes which occur long after the
experiment terminates.
3. The assertion that the authors are measuring DNA-protein
cross-links needs to be validated by actual
characterization of the DNA fractions by sensitive
analytical techniques. In this regard, other work has
shown that the great majority of radiolabel associated
with DNA after exposure of either "naked" DNA or tissue
culture cells to radiolabeled formaldehyde, in the
absence of the use of NaBHj, is noncovalently bound HCHO
(Beland, 1983). If NaBH4 is used, the adduct profile is
not altered (P.A. Beland, personal communication).
4. Caution is indicated when attempting to estimate isotope
ratios due to metabolic incorporation. For example, if
the isotope ratios observed in olfactory mucosal
interfacial DNA rather than those in respiratory mucosal
aqueous DNA are used to indicate the ratios resulting
from metabolism, similar to what is done for proteins by
the authors, the relationship of administered dose, and
"covalently bound" DNA is not deraonstrably nonlinear
throughout the entire dose range, especially when the
4-27
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"nonlinearity" between 6 and 2 ppm referred to by CUT
is examined. The authors indicate that olfactory
mucosal interfacial DNA contains no DNA-protein cross-
links, and since it is isolated by the same method as
respiratory mucosal interfacial DNA, it is likely to be
more structurally similar to respiratory mucosal
interfacial DNA and may therefore be the more
appropriate control for the endpoint of DNA-protein
cross-links. The result also demonstrates the
sensitivity of the experiment.
5. The paper as published cannot be adequately evaluated
because it excludes the gpeeifis activity of the.
administered dosasn. arad actual counts. Using these data
(provided to us separately by the authors), the specific
activity for the administered dose is much lower than
doses usually used for in vivo studies. The resultant
"DNA binding" is, however, quite high. For example, at
6 ppm, the binding is approximately one adduct per
10,000 nucleotides, approximately 10 to 100 times higher
than that observed in "naked" DNA or in tissue culture
for formaldehyde binding (Beland, 1984) or cross-links
(Wilkins and MacLeod, 1976); it is also very high when
compared to binding of even chronically administered
"strong" carcinogens with an intense biological effect
(Poirier et al., 1983; Swenberg et al., 1984). These
facts again urge caution in interpretation of the
measurements as S5NA-protein cross-links. Also, the (dpm
- background) values for a number of points, especially
those at the lower doses, are low (151, 176 for 3H, and
121, 123 for 14C at 0.3 and 2.0 ppm, for example),
necessitating special care in measurement and
interpretation.
Various studies have been undertaken to determine whether
HCHO has genotoxic effect in vivo. In mice, the dominant lethal
test was found to be negative (doses up to 40 mg/kg, IP).
However, in a more recent dominant lethal assay using higher
doses (SO mg/kg, IP) and a different ssouse strain, marginally
positive results were obtained, but only in the first and third
week of the seven weeks studied (Consensus Workshop on
Formaldehyde, 1984). However, the positive response obtained nay
not be indicative of a mutagenic change for the following
reasons:
4-28
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1. The week to week variation in implantations data are
common in dominant lethal studies. Therefore,
concurrent controls should be included in each weekly
mating. It is not clear from the paper how the control
matings were conducted; the control value is shown as a
mean with no indication of the extend of weekly
variation in control population.
2. The index of implantation deaths should probably be
analyzed on the basis of "per pregnant female" and not
on the total numbers as done in the paper.
3. Preimplantation losses as shown in week 1 and 3 should
be viewed as an index of dominant lethal effect only if
the losses were found to be due to death of preimplants
and not due to failure of oocytes to become fertilized.
(IRMC Report on Systemic Effects, 1984)
Negative results were obtained when the induction of micronuclei
or chromosomal aberrations were used as an endpoint. A small
increase in SCE's has been reported in the bone marrow of mice
exposed to high O25 ppm) HCHO concentrations. Unfortunately,
technical problems were encountered during the HCHO exposures,
and the actual concentrations required to elicit this effect are
not known (Consensus Workshop on Formaldehyde, 1984). In a
recent study by Ward Jr. et al. (1984) measuring changes in sperm
morphology, mice were treated by gavage with five consecutive
daily doses of formalin (100 mg/kg; 10 animals). No increase in
abnormal sperm morphology was obseved in the treated mice.
The possibility of genetic effects in humans caused by
inhalation of HCHO has been investigated by a number of persons.
In an unpublished study by Spear (1982), significant numbers
of SCE's in eight students exposed to HCHO during an anatomy
laboratory class were found. Mean HCHO levels were 1 ppm during
dissections. However, no genetic effects in humans were seen in
4-29
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studies by Fleig et al. (1982), Ward Jr. et al. (1984), and
Thomson et al. (1984).
In the study by Fleig et al. (1982), 15 employees exposed to
HCHO during HCHO manufacture and processing were studied. The
employees had 23 to 35 years of exposure. Mean HCHO levels did
not exceed 5 ppm before 1971 and 1 ppm after that date, with most
workers exposed to a maximum of 0.25 ppm (post 1971). No
increase in chromosome aberrations was observed as compared to
controls. Similarly, in a study of pathology staff exposed to
HCHO by Thomson et al. (1984), no difference in chromosome
aberrations induction and SCE frequencies was seen between the
exposed and control groups (6 exposed and 5 controls). Time-
weighted average levels of HCHO ranged from 1.14 to 6.93 mg/m3,
with peaks greater than 11.0 mg/m3. The pathology workers were
generally exposed to HfCHO for 2-4 hours per day, 2-3 days per
week. Finally, in the Ward Jr. et al (1984) study, sperm count,
morphology, and fluorescent body frequency in 11 autopsy service
workers exposed to HCHO and 11 controls were evaluated. Time-
weighted average HCHO levels ranged from 0.61 to 1.32 ppm (weekly
exposure range 3-40 pm hours). No significant differences in the
endpoints studied were observed between exposed and control
groups.
3|,4. Other 8ffacts/Defense Kechanisars
4.4.1. Introduction
The cancer response observed in the Kern et al. (1983) study
was very nonlinear, 1% of the rats responded at 5.6 ppm while 50%
4-30
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responded at 14.3 ppm. A number of hypotheses have been
developed which attempt to explain this response and the
different responses seen in rats and mice in that study. These
hypotheses are based on the noncarcinogenic effects of HCHO.
Although these noncarcinogenic effects are not easily separated,
it is possible to discuss them in three subject areas: sensory
irritation; cell-proliferation; and the mechanics of the mucous
layer "defense" system.
4.4.2. Sensory Irritation
In the Kern et al. (1983) study, the response observed in
mice as compared to rats is markedly different, 2 mice responding
at 14.3 ppm versus 103 rats responding at this concentration.
Also, in studies using hamsters (Dalbey et al., 1982), no tumor
response was seen. One of the reasons given for the difference
between rats and mice is the observation that mice exposed to
14.3 ppm reduce their breathing rate in response to the irritant
properties of HCHO. Such an effect may be occur ing in hamsters
at the doses tested, but experimental evidence is lacking. How
reduction in breathing rates (which is an effective defense
mechanism at certain concentrations) is weighed in terms of HCHO
cancer risk assessment is discussed below.
It is well established that sensory irritants evoke
responses by stimulating the free nerve endings of the afferent
trigeminal nerve located in the corneal, nasal, and oral
mucosa. Besides burning sensations, sensory irritants cause a
number of physiological reflex responses, one of which is a
4-31
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decrease in respiratory rate. A number of chemicals have been
studied in this regard and have RDSO's established for .them. The
RD50 value is that concentration of an irritant that causes a 50%
reduction in respiratory rate. A proposal to use RDSO's to
establish concentration standards for human exposure to sensory
irritants has been made (see Kane et al., 1979; and Buckley et
«!., 1984). A number of chemicals nave been investigated and
RD5Q values established? including HCHO and hydrogen chloride.
Consideration of this effect may be important in interpreting
inhalation bipassays because a doubling of a nominal
concentration to which an animal is exposed may not result in a
doubling of the dose actually received by the animal. For
instance, the RD50 value of HCHO for Swiss-Webster mice is 3.13
ppra. Consequently, results from a study using a dosing regimen
with concentrations above and below this number should be
interpreted in the light of the fact that the dose actually
received by the test animals does not increase in the same
proportion as the nominal concentration.
In the case of the Kern study, experimental data (Chang et
al., 1981; 1983) indicate that mice exposed to 14.3 ppm HCHO
•-reduced their breathing rate to such an extent that an adjusted
ft~ -
exposure concentration would show the mice being dosed with
-approximately the same amount ©f HCHO as rats at 5.6 ppm, where
the same cancer response was observed. If this factor is wholly
responsible for the difference in response between rats and
mouse, then adjusted doses can be used to calculate risks from
4-32
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mouse data. Thus, it can be postulated that if mice could be
exposed to levels of HCHO that would approximate the amount rats
received at 14.3 ppm, then the response in mice would be similar
and estimated risks would parallel those estimated from rat
data. If mice are less sensitive than rats to HCHO's
carcinogenic potential, then the risk would be less. However,
experimental data in this regard are lacking, and there is no
evidence that mice would be more or less sensitive to HCHO on a
dose received basis. Since experimental data regarding the
respiratory response of hamsters to sensory irritants is lacking,
one can only surmise from the bioassay data that hamsters are
less sensitive to HCHO's carcinogenic properties. EPA's proposed
guidelines address this point by stating, "Because it is possible
that human sensitivity is as high as the most sensitive
responding animal species, in the absence of evidence to the
contrary, the biologically acceptable data set from long-term
animal studies showing the greatest sensitivity should generally
be given the greatest emphasis, again with due regard to
biological and statistical considerations." It should be noted
that all the rat inhalation studies of HCHO (Kern et al., 1983;
Albert et al., 1982; and Tobe et al., 1985) had comparable
response rates at 14 ppm HCHO. If one looks at the cancer data
for acetaldehyde, one sees roughly comparable responses in
hamsters and rats at similar dose levels, although the anatomical
location of the effects are different. This raises the
possibility that the carcinogenic response of hamsters and rats
4-33
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to closely related aldehydes may be similar. However, much data
needs to be developed in this regard.
In conclusion, the weight of the evidence indicates that
mice are more sensitive to the sensory effects of HCHO than rats,
and it may be this response which accounts for the different
carcinogenic response observed in rats and mice in the Kern et
ale {1983} study. Adjusting dose levels for this response shows
that saice may be as sensitive as rats to the carcinogenic
potential of HCHO. Hamsters, on the other hand, appear to be
less sensitive to HCHO, although the response of hamsters and
rats to acetaldehyde is similar, which presents the possibility
of comparable responses to HCHO (as discussed in the section on
animal tests, two factors may account for the absence of an
observed effect in hamster; pathology, and the lack of a multi-
dose test). Consequently, as provided for in the Guidelines, the
selection of the rat data for risk estimation purposes is
Justified.
Finally, although a reduction in respiratory rates is a
defense mechanism at certain concentrations and above, its
practical importance to low-dose risk estimation is nil provided
that when quantitative risk estimation is done, dose levels are
^adjusted* if necessary, to reflect the actual dose received
'-thereby ensuring an accurate dose-response. This defense
rpechanism is not indicative of a threshold or nonlinearity at low
-?*' . • •
^doses.
4-34
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4.4.3. Cell Proliferation, Cytotoxicity, and the Mucous Layer
Another important consequence of HCHO's irritant properties
is its effects on cell proliferation and damage it can cause to
the raucociliary clearance system (respiratory and olfactory
epithelium) of the nasal cavity. These effects have been cited
(Starr et al., 1984) as important factors in HCHO induced
carcinogenicty from the standpoint of their impact on the
mucociliary clearance system, as a prerequisite for HCHO induced
cancer, and in understanding the importance of concentration
versus cumulative exposure. These factors have an important
impact on the model chosen for quantitative risk assessment and
the weighing of noncarcinogenic effects as a cancer risk factor.
4.4.3.1. Cell Proliferation and Cytotoxicity
Studies by Swenberg et al. (1983) and Chang et al. (1983)
have reported the relationship between HCHO concentration and
cumulative exposure on cell turnover in the nasal cavity of rats
and mice. A diagram indicating the coding of the nasal cavities
of rats and mice for the test data discussed below is provided in
Figure 4-3.
4-35
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figure 4-3. Drawing indicating the level of sections from
the nasal passages of rats and mice. Figure taken from
Swenberg et al. 1983.
In one test, rats and mice were exposed to 0, 0.5, 2, 6, and 15
ppm HCHO 6 hrs/day for 3 days, and then to ^H-thymidine 2 hours
after the end of exposure. As illustrated in Table 4-4,
increased cell proliferation as measured by increased
incorporation of labelled thymidine into cells was evident in
rats at 6 and 15 ppm and in mice at 15 ppm.
Table 4-4.
EFFECT OP FORMALDEHYDE EXPOSURE ON CELL PROLIFERATION
IN LEVEL B OF THE NASAL PASSAGES*
Exposure*
Control
0.5 ppm
2 ppm
€ ppm
15 ppm
% of Labelled Respiratory
Rat
0.22 ^ 0.03
0.38 i 0.05
0.33 ± 0.06
5.40 +. 0.82
2.83 ^ 0.81
Epithelial Cells***
Mouse
0.12 ± 0.02
0.09 ± 0.04
0.08 '± 0.04
0.15 ± 0.06
0.97 ± 0.04
•Table taken from Swenberg et al. (1983).
**All animals exposed for 6 hrs/day for 3 days.
***Mean + standard error.
4-36
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Wnen tne labelled thymidine is administered 16 nours after
the last exposure, a greater increase in cell turnover is seen as
illustrated in Table 4-5. The increase in cell labelling may be
because 2 hours post exposure may not be the most sensitive time
for DNA synthesis due to initial inhibition by HCHO (Swenberg et
al., 1983).
Table 4-5.
EFFECT OF THE TIME OF *B-THYMIDINE PULSE ON CELL
REPLICATION AFTER BCUO EXPOSURE TO RAT*
Post-Exposure
Tine of Pulse
2 hours
18 hours
% Labelled
O/ppm
0.26 ± 0.03
0.54 +. 0.06
Cells**
6 ppm"«
1.22 ± 0.17
3.07 _+ 1.09
*Table taken from Swenberg et al. (1983).
**Mean jf_ standard error.
***6 ppm, 6hr/day for three day.
To determine whether concentration is more important than
cumulative dose, a series of concentration time products were
tested. Each product equaled 36 ppm-hrs of exposure. The
results of this test, which appear in Table 4-6, indicate that,
at least for the effect measured, concentration has a greater
affect in level B of the rat nasal cavity.
4-37
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Table 4-6.
EFFECT OF ECHO CONCENTRATION vs. CUMULATIVE
EXPOSURE ON CELL TURNOVER IN RATS (Level B)*
% Labelled Cells*
Exposure 3 days + 18 hrs 10 days + 18 hrs
Control 0.54 ± 0.03 0.26 +_ 0.02
3 ppm X 12 hrs 1.73 +. 0.63 0.49^0.19
6 ppm X 6 hrs 1.07 ± 1.09 0.53 +. 0.20
12 ppm X 3 hrs 9.00 £ 0»89 1.73 ± 0.65
•Table taken from Swenberg et al. (1983)
**Mean +_ standard error.
However, the amount of labeling measured in the most
anterior region of the nasal cavity indicates the opposite. The
extent of labeling was essentially the same at each HCHO exposure
level. See Table 4-7 for details.
Table 4-7.
EFFECT OF BCHO CONCENTRATION VS. CUMULATIVE
EXPOSURE ON CELL TURNOVER IN RATS (Level A)*
% Labelled Cells
Exposure . After 3 Days Exposure**
Control 3.00 +_ 1.56
3 ppm X 12 hrs 16.99 ^ 1.50
6 ppm X 6 hrs 15.46 +_ 10.01
12 ppm X 3 hrs 16.49 ^ 2.07
•Table taken from Swenbery et al. (1983)
**Mean + standard error.
4-38
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Whether this difference in cell proliferation between levels
A and B is due to differences in roucocillary clearance in the
respective regions, to HCHO-laden mucous flowing from posterior
to anterior regions (Swenberg et al., 1983) or simply that the
"capture" capacity of Level A is exceeded which allows pass-by of
HCHO to Level B and beyond, or some other reason, is unknown.
The data developed on mice regarding cell proliferation are
not as clear. In a test to measure differences between
concentration and cumulative exposure there was an inverse
response as illustrated in Table 4-8.
Table 4-8.
EFFECT OF HCHO CONCENTRATION vs. CUMULATIVE
EXPOSURE ON CELL TURNOVER IN MICE (Level A)*
% of Labelled Cells
Exposure After 10 Days Exposure**
Control 1.24 _4_ 0.57
3 ppm X 12 hrs 10.14 .+ 3.20
6 ppm X 6 hrs 4.72 +_ 1.61
12 ppm X 3 hrs 1.76 +_ 0.49
*Taole taken from Swenberg et al. (1963).
**Mean ^ standard error.
The difference between rats and mice has not been adequately
explained, except that there appears to be a significant species
difference regarding cell proliferation.
A study by Rusch et al. (1983) supports the concept that
concentration may be more important than cumulative exposure, at
4-39
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least for rats. In the study, five groups of 6 male Cynomologus
monkeys, 20 male and 20 female Fischer 344 rats, and 10 male and
10 female Syrian golden hamsters were exposed to 0, 0.2, 1.0, and
3.00 ppm for 22 hrs per day, 7 days per week for 26 weeks.
The most significant finding was squamous metaplasia/
hyperplasia in rats and monkeys at 3.0 ppm. Hamsters were not
affected at any dose level. However, the most significant
finding is that even though rats at 1,0 ppm in the Rusch et al.
(1983) study received a cumulative exposure 2.5 times greater
than rats at 2.0 ppm in the Kern et al. (1983) study, which
experienced squamous metaplasia, they were largely free of
squamous metaplasia. This strengthens the conclusion of the
Swenberg et al. (1983) study which indicates that, at least for
rats, concentration is more of a factor than cumulative exposure.
In the Kern et al. (1982) study, significant levels of
noncarcinogenic lesions were noted in rats at all dose levels.
The severity and extent of these lesions were concentration and
time dependent and seem to be correlated with the cancer
response, i.e., these lesions preceded the appearance of squamous
cell carcinomas and their severity increased with increasing
cancer response. This observation, tied with the data showing
ineraas*® in cell proliferation due to HCHO exposure and a
;-' ~£ ' • ~
threshold for squamous hyperplasia/metaplasia of between 1 and 2
ppm, leads some to the hypothesis that there is a threshold for
HCHO'8 carcinogenicity or that the dose-response is nonlinear at
low doses. Another factor suggested to contribute to the
4-40
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possibility of a threshold between 1 and 2 ppm HCHO, is the role
of the mucous layer in trapping and removing HCHO in this
range. This hypothesis is that when its removal capacity is
exceeded, HCHO can then impact the respiratory epithelium, thus
causing the noncarcinogenic effects noted above. A discussion of
the role of the mucous layer follows this section.
As noted previously, there was a 50 fold increase in cancer
response due to a slightly more than a doubling of the dose in
the Kern study (5.6 to 14.3 ppm). What was the change in
response of the noncarcinogenic effects? Using data developed
for the incidence of squamous metaplasia in rats in the Kern
study, a comparison can be made. The incidence of squamous
metaplasia in level 2 of the rat nasal cavity was chosen because
it showed a positive correlation with concentration rather than
cumulative dose, moreover, it is in the middle of the anterior
part of the nasal cavity where the squamous cell carcinomas were
observed, and it is of the same cell type as the carcinomas. If
one compares the percentage incidence of squamous metaplasia in
the three dose groups at the sacrifice points in Table 4-9, one
sees a clear dose-response, but not a 50 fold increase between
5.6 and 14.3 ppm; there appears to be only a 2 fold increase or
less. While increased cell turnovers could lead to greater
interaction of HCHO and single-strand DNA, and thus an
enhancement of the cancer response, the data on the incidence of
squamous metaplasia alone do not appear to explain the extreme
nonlinearity observed.
4-41
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Table 4-9.
FREQUENCY OF SQUAMOUS METAPLASIA IN LEVEL 2
Uf THE RAT NASAL CAVITY*
Incidence (Percent) of Squamous Metaplasia
Dose (ppm)
6
50
75
Month of
12
45
90
Sacr
18
60
98
if ice
24
65
100
27
30
100
5.6
14.3
*Estisnated from Figure 4~lo.
Other chemicals such as acetaldehyde, hexamethyphos-
phor amide (HMPA), are cytotoxic and cause cancer in rats. What
can the data on these chemicals tell us?
If one examines the incidence and severity of the
noncarcinogenic lesions seen in the Feron et al. (1984)
acetaldehyde study and the tumor response, one sees a roughly
dose-related response, i.e., a doubling of dose doubles the
response seen (cancer and noncancer). Although the olfactory
epithelium was severely affected at the highest dose, the cancer
response is hardly increased over the next lower dose (see the
section on structure Activity Relationships for a full discussion
of the data on acetaldehyde).
An anatamical region that had a high incidence of noncancer
.that were dose-related was the larnyx (mostly squamous
metaplasia). Table 4-10 illustrates this response. However,
only one tumor was observed in the larnyx.
4-42
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Table 4-10.
INCIDENCE OF LESIONS OTHER THAN TUMORS
IN THE LARNYX OP RATS EXPOSED TO
ACETALDEHYDE (NUMERIC]*
Dose (ppm)
0
50
3
1
750
50
6
4
1500
51
23
13
3000/1000
47
41
32
Number of Male Rats
Squamous metaplasia
Hyperkeratosis
*Data from Feron et al. (1984)
Finally, the relationship between the noncancer and cancer
response seen in rats exposed to HMPA is unremarkable. As Table
4-11 indicates, an increase in dose did not lead to a many fold
increase in the cancer response although HMPA severely damaged
the nasal mucosa of the rats.
Table 4-11.
INDIGENCE OF EPIDERMOID AND ADENOID SQUAMOUS
CARCINOMAS IN RATS EXPOSED TO
HEXAMETHYLPHOSPHORAMIDE*
Dose (ppb)
No. of Rats
Examined
Epidermoid carcinoma
Adenoid squamous
carcinoma
0 10 50 100 400 4,000
396 200 194 200 219 215
Tumor Incidence (%)
0 0 12.4 29.5 62.6 55.8
0 0 2.1 2.5 9.6 19.1
•Data from Lee et al. (1982)
4-43
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As a general matter, it appears that there is no clear
relationship between cell proliferation/cytoxicity and tumor
response. It is clear that there is much variation in the way
tissues respond to carcinogens, and no firm conclusions can be
drawn. The appearance of noncancer lesions is not surprising
given the acute toxicity of many carcinogens. However, it is
impossible at this time to clearly link the noncancer effects in
the Kern study to .the appearance of cancers and the nonlinearity
of the response. On the other hand, it is plausible that the
noncancer effects may enhance the cancer response of HCHO and
other carcinogens by providing an increased opportunity to
interact with single-strand DNA during cell replication or to
promote an initiated cell. Consequently, prudence would dictate
that exposure at levels that cause cell proliferation or lesions
be avoided. This includes short-term peaks especially if
concentration is more important than cumulative dose. Also, it
must be remembered that there is a natural background rate of
cell turnovers in the nasal mucosa which can provide the
opportunity for mutagenic/carcinogenic events to occur. Although
such events may be rare, only one such sequence of events may
need to occur in a population of 10,000 persons over 70 years to
give a cancer risk, of 1 X 10~4.
Finally when discussing acute responses to a chemical such
as irritating effects, it should be remembered that there can be
a no-effect level at or below which no response is observed no
matter how many days of exposure occur. However, once a minimum
4-44
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effect concentration is reached, the duration of the exposure may
have a major impact on the severity of the effect. Although the
occurrence of squamous metaplasia and other responses to acute
effects may influence the expression of a carcinogenic response,
the absence of these acute responses does not signify a no-effect
level for a carcinogenic response.
4.4.3.2. Mucous Layer
Besides HCHO's effect on cell proliferation and respiratory
response, it also has a major impact on the mucociliary system of
the nasal cavity through its irritation and cell killing
properties at elevated concentrations. In addition, it has been
postulated that below certain HCHO concentrations (1-2 ppm) the
mucous layer can trap and remove inhaled HCHO, thus preventing it
from reaching underlying cells. However, once the removal
capacity of the mucous layer is exceeded, HCHO can then begin to
affect the underlying cells as described in the section above.
If the mucous layer removed inhaled HCHO below 1 ppm then it
would represent a threshold phenomenon at least for the nasal
cavity. However, the evidence for this is lacking and the idea
is directly contradicted by experimental data. The discussion
below describes the effects caused by HCHO on the mucocilary
system and the support for the "barrier" action postulated.
The nasal cavity is primarily composed of ciliated
respiratory and olfactory epithelium which is covered by a moving
blanket of mucus. Mucus is composed of approximately 95% water
and 0.5-1% glycoproteins and other minor constituents. The human
4-45
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nose has tnree functions, two of which depend on the presence of
a mucous layer. The first function of the nose is to inform us
of the presence of noxious gases, if these stimulate the
receptors of the olfactory nerves. The second function of the
nose is to drain the secretions of the sinuses and of the
lacrinal (tear) glands. The third function of the nose is to
prepare the inhaled air for the lungs. This includes warming,
aoistenlng? and filtering inspired air. Dust and many bacteria
found in the inspired air are precipitated in the mucous that
bathes the mucous membrane and, by the action of the cilia of the
nasal passage, are moved outward (Tuttle et al., 1969).
As research by Morgan et al. (1983a, 1983b, 1984) indicates,
HCHO has a number of effects on the workings of the mucociliary
apparatus. Using in vitro and in vivo techniques, Morgan et al.
(1983a) examined mucous flow patterns in the rat nasal cavity and
the effect of HCHO on the mucociliary apparatus. Results of the
in vitro analysis indicate that mucus was present as a flowing
continuous coat over the respiratory epithelium except on the
most anteriorcentral extremity of the nasoturbinates and the
anteriomedial extremity of the maxilloturbinates. Mucous flow
rates ranged from 0.28 to 9.02 mm/minute. When rats were exposed
to IS ppa HCHQe
-------
dose-dependent affect on mucociliary activity. At 15 ppm there
was significant inhibition of mucociliary activity which
progressed from anterior to posterior regions of nasal tissue.
Only slight effects were noted in animals exposed to 2 or 6
ppm. At 0.5 ppm no effects were observed. Finally, using frog
palate, Morgan et al. (1984) found that mucous stasis, and
ciliastasis occurred at 4.36 and 9.58 ppm, respectively. At 1.37
ppm an initial increase in ciliary activity was observed but
there was no mucous stasis or ciliastasis, while at 0.23 ppm
there was no effect.
The above results indicate that a concentration relationship
exists where mucociliary flow would be impaired at 15 ppm and
less so at 6 and 2 ppm. This range corresponds to the range
where the steep dose-response in carcinogenicity of HCHO was seen
in the Kern et al. (1983) study. Whether the mucous layer has
some finite capacity to absorb HCHO and wash it away to prevent
it from reaching the underlying cells, or the response seen is
simply the overt signs of gradual cell toxicity, is unknown.
However, a number of factors must be considered when discussing
the protective ability of the mucous layer. First, humans can
detect HCHO at levels below 1 ppm which indicates that, at least
in the olfactory region of the nasal cavity, HCHO is not
completely removed by the mucous layer. The mucous layer is
reported to be immobile or flowing extremely slowly in this
region (CUT, 1984). However, it would seem that if a greatly
reduced removal capacity of the mucous layer in the olfactory
4-47
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region played a role, this region should have been a target for
effects in the Kern et al. (1983) study. This was not .the
case. The significant neoplastic and nonneoplastic effects were
generally seen in the anterior regions of the rat nasal cavity.
Second, in a study by Casanova-Schmitz et al., 1984), which
measured the difference between metabolic incorporation and
eovalsnt binding of labelled ECHO to macremolecules, it was found
that eovalent binding to protein increased in a linear manner
with increases in airborne concentrations (0.3 - 15 ppm). These
data do not support the concept that at doses lower than 1-2 ppm
the mucous layer can act as a sink for inhaled HCHO which
prevents it from reaching underlying cells.
Finally, no data have been presented that show that HCHO is
bound and removed by the mucous layer. This is not to say that
the raucous layer has no capacity for HCHO removal, but in the
face of no pertinent data in this regard and the results of the
Casanova-Schmitz et al. (1984) study discussed above, it must be
concluded, at this time, that there is little support for a
threshold effect due to the mucous layer. Although it is clear
that HCHO disrupts the mucociliary system, this is more likely
due to a gradual poisoning of mucosal cells once the thresold for
^eieterious effects is reached, and not because the removal
capacity is exceeded.
4.4.3.3. Conclusion
In conclusion, it is consistent with some of the data
described above to assume that HCHO's irritant and cytotoxic
4-48
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properties may have contributed to the nonlinearity of the
malignant tumor response seen in the Kern et al. (1983) study.
HCHO's demonstrated ability to increase cell turnover could
provide greater opportunity for HCHO to interact with nuclear
material. As the concentration of HCHO increases, greater cell
proliferation and cell death occur which provide even more
opportunities for HCHO-DNA interactions. To what degree the
mucous layer protects against HCHO's cytotoxic effects is not
clear, but the experimental data do not suggest a large role for
this. Although it seems probable that some HCHO could react with
protein in the mucous layer, data have not been developed to show
that the ratio between the airborne concentration and the amount
entering target cells is nonlinear, on the contrary, data have
been developed to show that it is linear. (Data relevant to the
formation of HCHO-DNA adducts is discussed in another section—
Short-Term Tests-Mutagenicity.) Regarding the impact of changes
in respiratory response to sensory irritants, it is likely that
this response is responsible for the different response of rats
and mice in the Kern et al. (1983) study. Also, other data
presented by Swenberg et al. (1983) indicate that rats only
inhaled twice as much HCHO at 15 ppm as they did at 5.6 ppm,
which indicates that the dose-response curve may be even steeper
when tissue dose is plotted rather than concentration.
Thus, it seems likely that many of the factors outlined
above have contributed to the differences seen among species in
their response to HCHO as well as the steep dose-response seen in
4-49
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the. Kern et al. (1983) study. However, an examination of the
data described in the sections above (1) does not support the
concept that the action of the mucous layer presents a "oarrier"
to HCHO and thus a threshold for its carcinogenic effects, (2)
that the appearance of and severity of noncancer lesions can be
used to predict the nature of the cancer response, and (3) that
the appearance of noncancerous lesions is a necessary
prerequisite for cancer Induction»
4.5. Metabolism and Pharaacokineti.es
4.5.1. Absorption
HCHO can enter the body as a result of inhalation,
ingestion, or dermal absorption. Absorption of HCHO through the
upper respiratory tract in dogs has been" estimated to exceed 95%
of the inhaled dose (Egle, 1972). Studies by Heck et al. (19*83)
indicate that roost of the radiolabel from radiolabelled HCHO
inhaled by rats was found in tissues from the anterior portion of
the nasal cavity (the concentration was 10-100 fold greater than
other tissues). Radiolabel was found in other tissues, but it is
unlikely given HCHO's rapid metabolism that the radiolabel found
was HCHO. In another study by Heck et al. (1982a), the quantity
of HCHO was measured in rat tissue before and after inhalation of
HCHO or ehlorcm©thane. The analytical method used cannot
•
distinguish between free and bound HCHO. Measured HCHO
concentrations were as follows; 0.42 umol/g for nasal roucosa,
0.097 umol/g for brain, an 0.20 umol/g for liver. Inhalation of
€ ppm HCHO for 6 hrs/day for 10 days did not significally alter
4-50
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the nasal mucosa HCHO concentration. Following oral exposure of
dogs to HCHO, formate levels in the blood increased rapidly,
indicating rapid uptake and metabolism (Malorny et al., 1965).
Dermal absorption has been demonstrated in guinea pigs (Usdin and
Arnold, 1979), but does not appear to be significant in
comparison to inhalation or ingestion. studies have also
demonstrated the dermal absorption of I14C] HCHO in rats and
monkeys, and rabbits, respectively (Ulsamer et al. 1984). The
chemical form of the radiolabel has not been determined, but it
has been reported by Ulsamer et al. (1984) that data from in
vitro diffusion studies using rabbit skin indicate that free HCHO
cannot be detected enzymatically.
4.5.2. Pharroacokinetics
4.5.2.1. Conversion to formate
HCHO that enters the body appears to be converted rapidly to
formate and CO2 (Malorny et al., 1965; HcMartin et al., 1979) or
to combine with tissue constituents. The conversion of HCHO to
formate occurs following intravenous (i.v.) infusion,
subcutaneous injection, gastric intubation, or inhalation.
Studies using i.v. infusion of 0.2M HCHO to dogs have shown that
only a small amount of HCHO appears in the plasma during exposure
(Malorny et al., 1965). This becomes undetectable within 1 hour
after cessation of infusion. The peak formate concentration
following HCHO infusion was the same as when formate (0.2M)
itself was infused. The plasma half-life for formate (between 80
and 90 min.) was also similar. In the same study, HCHO could not
4-51
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be detected after oral administration of 0.2M HCHO, although
formate increased rapidly in the plasma with a half-life of 81.5
minutes.
Similar experiments using Cynomolgus monkeys, in which 0.2M
HCHO was infused i.v., showed no accumulation of HCHO in blood
(McMartin et al., 1979). The blood half-life was estimated to be
1»S rainutes. Similar half-lives for blood HCHO have been
observed in rats, guinea pigs? rabbits, and cats (Rietbrock,
1969). Studies by Heck (1982b) have shown that 114C] formate and
114C] HCHO have similar distribution patterns in rat blood cells
and plasma following i.v. injection, and follow the same decay
curve. In a somewhat different experiment, McMartin et al.
(1979) administered C14-labelled methanol by gastric
intubation. Again, HCHO could not be detected in the blood
although formate levels increased rapidly. A study in which
humans were exposed to HCHO gas (0.78 mg/m^) for 3 hours also
demonstrated a rapid rise in blood and urine formate levels
(Einbrodt et al., 1976). In a more recent study by Heck et al.
(1985), HCHO concentrations in the blood of rats and humans were
investigated. The rats (8 exposed and 8 controls) were exposed
to approximately 14.4 ppm HCHO for 2 hrs. Blood was collected
immediately after exposure and analysed by gas chromatography/
•ass spectr©photometry. No significant differences were seen
between exposed and control rats. Six human volunteers (4M, 2F)
were exposed to 1.9 ppm of HCHO for 40 minutes. Venous blood was
analyzed for HCHO levels before and after exposure. There was
4-52
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not a statistically significant effect of exposure on tne average
HCHO blood concentrations of the volunteers. However,
significant differences were seen in some of the subjects'
(either decrease or increase) HCHO concentration between blood
taken before and after exposure.
The rapid conversion of HCHO to formate occurred in many
tissues in the various species examined, including human .
erythrocytes (Malorney et al., 1965), liver and brain; sheep
liver; rat brain, kidney, and muscle, rabbit brain; and bovine
brain and adrenals (Uotila and Koivusalo, 1974). The enzymes
involved have been studied by Strittmatter and Ball (1975) as
well by Uotila and Koivusalo (1974). The oxidative process is
initiated by formation of S-formyl glutathione, which is then
oxidized by NAD and finally cleaved by thiol esterase, releasing
formic acid and glutathione. HCHO also has been reported to be
oxidized to formic acid by a nonspecific aldehydehydrogenase and
through the tetrahydrofolic acid pathway (Huennekens and Osborn,
1959).
4.5.2.2. Conversion to CO2 and other metabolites
Additional studies (DuVigneaud et al., 1950) have shown that
following subcutaneous administration of 14C-HCHO to rats,
approximately 81% of the radioactivity was found in choline.
Almost 60% of a subcutaneous dose of 14C-formate appeared as
l4CO2f with small amounts of radioactivity in choline. Neely
(1964) administered radiolabelled HCHO intraperitoneally (i.p.)
to rats and found that 82% of the radiolabel was recovered as C02
4-53
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and 13-14% as urinary methionine, serine,.and a cysteine
adduct. At lower doses, only radiolabelled methionine .was
formed. The author postulated that CO2 was derived from serine
(formed from glycine and N5,N10 methylene tetrahydrofolate) by
deamination to pyruvate and oxidation in the Krebs cycle. In a
study by Mashford et al. (1982), it was found that in rats
administered 4 mg/kg of radiolabelled HCHO,, most was exhaled
within 48 hrs as CO2f 5*5% was found in the urine. At a dose 10
tines higher (40 mg/kg), 78% was exhaled as CO2 after 48 hrs,
while 11% was found in the urine. When HCHO was administered to
rats by inhalation, 40% of the radiolabel was found in tissues,
40% was exhaled, and 20% appeared in the urine (Heck, 1982b). it
was found by Heck (1983), that the greatest amount of radiolabel
in the rat nasal mucosa was found in RNA? with a lesser amount in
protein and a small amount in DNA.
The formation of methionine from 14C-HCHO and homocysteine
had previously been demonstrated by Berg (1951). Formation of
roethionine would also account for the labelled choline observed
by Duvigneaud et al. (1950) via methylation of phosphatidyl
ethanolamine. More recent work by Pruett et al; (1980) has
demonstrated the incorporation of 14C-HCHO into the nucleic acid
and protein fractions of in 38 human diploid fibroblasts. Most
of the radiolabel was found in RNA with lesser amounts in DNA and
protein. The purine bases of both DNA and RNA were most heavily
labelled. Besides being converted rapidly to CO2 and formate,
and being incorporated into other chemicals, HCHO can alkylate
4-54
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macromolecules such as ajr.ino acids, proteins, nucleotioes, and
ONA (Ulsamer et al., 1984). Casanova-Schmitz et al. (1984) have
determined that DNA-protein cross-links are the only important
reaction products of HCHO with DNA, but this assertion has been
questioned by Conn et al. (1985).
In addition to the serine pathway to C02 postulated above
(Neely, 1964), two other pathways have been identified, and are
diagrammed in Figure 4-4.
10-FcnByttnnArarafoUu
NADH-IT
w.
KCiO _., __._.
«> ^\
tCOOH
Figure 4-4. simplified reaction sequence from drug
N-deraethylation (cytochrome-P-450-dependent monooxygenase)
to HCHO, formate, and CO, production (from Waydhas et al.,
1978). Reactions are: la, HCHO dehydrogenase (GSH);
Ib, aldehyde dehydrogenase; Ic, catalase (peroxidatic
mode); 2a, 10-formyltetrahydrofolate synthetase; 2b,
10-forroyltetrahydrofolate dehydrogenase; 2c, catalase
(peroxidatic mode).
4-55
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Waydhas et al. (1978), McMartin et al. (1977;/ ano Palese
and Tephyl (1975) have demonstrated that the catalase reaction
(Figure 4-4) is not of major importance and that the primary
pathway to CC>2 from formate occurs via the tetrahydrofolic acid
pathway. This has been demonstrated in rat liver perfusates
(Waydhas et al., 1978) monkeys (McMartin et al., 1977), and rats
(Palese and Tephly, 1975K Since the tetrahydrofolic acid
pathway (Figure 4-5, from Kitchens et al., 1976) can lead to the
transfer of the carbon from formate to a number of other
compounds (including serine), it is not clear that the
10-formyltetrahydrofolate denydrogenase reaction (Figure 4-4) is
the only reaction of importance for CC^ production in this
pathway.
4-56
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Hlstldlrw
ATP
ATP
Inotlnlc
•eld »nd
purlflM
S«rlnt
•4* ItOQBl < — * **4 < i f
vt T
Monocy»t*In«
VIT. B
12
/-
Thymidyllc
•eld
MctMontnc
•nd
Compound*
P44 • t«tr«hydpofol le acid
f!0fH4 • MIO-fcr»yrt«tr»bydrotoMe acid
«etd
»eld
-fon>l«liiot«tr«hydrofolle «eld
Figure 4-5. Tetrahydrofolic acid pathway and 1-carbon
transfer for HCHO metabolism.
4-57
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4.5.2.3. Endogenous HCKO
Endogenous HCHO is primarily produced from the degradation
of serine with some contribution from the degradation of other
amino acids. Oxidative demethylation of N,N-dimethylglycine
(from choline degradation) also contributes significantly to
endogenous HCHO. Cytochrome p-450-dependent N-demethylation of
drugs can contribute additional HCHO. The rate of HCHO oxidation
to formate exceeded the rate of HCHO production in perfused rat
liver by a factor of 12 when aminopyrine was used as the
substrate for the demethylation reaction. Other xenobiotics
including dihalomethanes , methanol, diroethylnitrosamine,
hexamethylphosphoramide (HMPA), bis(chloromethyl) ether (BCME),
dibromoethane, and dimethylsulfoxide lead to the production of
HCHO. HCHO is also formed in vitro in the presence of an amine
acceptor, apparently by nonenzymatic breakdown of
N^,N*^-methylene-tetrahydrofolate This reaction produces
alkaloids from biogenic amines or drugs in vitro and probably in
vivo.
Whereas the conversion of HCHO to CO2 occurs in a similar
manner in the different, species studied, the relative importance
of each reaction differs among species and tissues. Thus, the
rat is able to convert formate to CO2 at more than twice the rate
of monkeys (or humans) and, as a result, has lower blood formate
levels (McMartin et al., 1977) and does not excrete formate in
the urine (Neely, 1964). Man additionally possesses 50% more
hepatic dehydrogenase than do rats (Goodman and Tephly, 1971).
4-58
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Den Engelse et al. (1975) have shown that mouse (C3Hf/A) and
hamster (Syrian golden) lungs do not convert formate to C02 as
efficiently as liver tissue does.
4.5.3. Summary
In summary, free HCHO is not usually found in plasma or
other body tissues in measurable quantities, endogenous HCHO that
is produced may be reasonably presumed to be metabolized rapidly
to formate or to enter the one-carbon pool. When exogenous
exposure does occur, HCHO is likewise rapidly metabolized to
formate and excreted, converted to C02 and/or incorporated into
other molecules. The same pathways seem to occur in all
mammalian species examined to date, but reaction rates differ
among various species and tissues. Neither the ratio of
metabolic deactivation to binding (to tissue or small molecules)
nor the effect of route of exposure on this ratio is known at
this tine. Thus, although Egle's work (1972) suggests that the
respiratory tract tissues would receive the greatest dose, other
body sites cannot be ruled out.
The overall metabolism of HCHO is summarized in Figure 4-6
(adopted from Kitchens et al., 1976):
Prottias tad tfuclftic Acids
Buclsic Acids
Ltbilt Mthyl groups
mad one carbon Mtabolii
CO,
Uriat AS Sodium Salt
Figures 4-6. Overall metabolism of HCHO (from Kitchens
et si., 1976)•
4-59
-------
As can be seen from Figure 4-6, HCHO is more chemically
active than any of its direct metabolites and would, therefore,
appear to be the chemical substance of most concern for
carcinogenicity. The possibility exists, that the actual
carcinogenic agent may be an amino acid (or other) adduct (EPA,
1981).
4.6. Structure-Activity Relationships
HCHO is structurally similar to other aldehydes such as
acetaldehyde, malondialdehyde and glycidaldehyde. These
aldehydes have been shown to have oncogenic activity in
laboratory animals. For instance, inhalation of acetaldehyde has
produced tumors of the nose and larynx in hamsters and tumors of
the nose in rats, when administered by inhalation, and
glycidaldehyde has produced skin tumors in mice in skin painting
tests. Since acetaldehyde is the closest in structure to HCHO,
and its effects on animals have been compared in a previous
section, the significant studies related to its oncogenic
potential will be described.
Acetaldehyde was not mutagenic in the standard Ames test
using Salmonella typhimurium (Commoner, 1976) and Escherichia
coli WP2uvrA (Hemminki et al., 1980). It had weak mutagenic
activity in the fruit fly Drosophila melanogaster (Rapoport,
1948). The potential of acetaldehyde to damage chromosomes has
been indicated by the dose-dependent sister chromatid exchanges
in the Chinese hamster ovary cells (Obe and Ristow, 1977) and
human lymphocyte cells (Ristow and Obe, 1978).
4-60
-------
The carcinogenic effects of the inhalation of acetaldehyde
vapor were studied in hamsters by Feron (1979). Male hamsters
were exposed to 1500 ppm acetaldehyde vapor (7 hr/day, 5 days/wk)
alone or simultaneously with benzo(a)pyrene (BP) as a weekly
intratracheal injection for 52 weeks. The weekly concentrations
of BP used were 0.0625, 0.125, 0.25, 0.5, and 1.0 rag/animal. The
maximum dose of BP administered throughout the entire experiment
was 52 rag/animal. Control animals were exposed to air alone or
simultaneously with the same concentrations of BP. At the end of
the treatment period, 5 randomly selected animals from each group
were killed and autopsied. All remaining animals were allowed to
recover for 20 weeks and sacrificed by week 72.
Exposure of hamsters to 1500 ppm acetaldehyde vapor produced
abnormalities in the respiratory tract which were characterized
primarily by reversible hyperplastic, metaplastic, and
inflammatory changes. Neoplastic alterations attributable to
acetaldehyde exposure alone were not found. Intratracheal
instillation of the highest dose of BP (52 mg, 1 mg/wk for 52
weeks) combined with inhalation of acetaldehyde produced twice as
many tracheal tumors (squamous cell carcinoma and squamous
adenocarcinoma) and a shorter latent period as intratracheal
instillation of BP alone. However, such a synergistic effect of
acetaldehyde was not noticeable at any of the lower BP levels.
No significant differences in the number of tumors in the larynx,
bronchi, bronchioles, or alveoli were found among the different
treatment groups.
4-61
-------
In a separate experiment, male and female hamsters were
treated intratracheally with acetaldehyde for a period of 52
weeks. The intratracheal instillations were given either weekly
or fortnightly with acetaldehyde (2% and 4%) alone or in the
presence of either BP (0.25% and 0.5%) or diethylnitrosamine
(DEN, 0.5%), two proven carcinogens. Interim sacrifices of 3
animals/ses/group were performed after 13, 26, and 52 weeks. All
remaining animals were sacrificed after 104 weeks.
Intratracheal administration of acetaldehyde at both dose
levels caused severe hyperplastic and inflammatory changes in the
bronchioalveolar region of the respiratory tract; however, only
one case of pulmonary adenoma was found out of 134 animals
treated with acetaldehyde alone. This is not considered to be an
indication of carcinogenic activity of acetaldehyde. Despite the
high degree and frequency of peribronchiolar adenomatoid lesions
found following intratracheal instillation of acetaldehyde, the
neoplastic response of the bronchioalveolar tissues was clearly
lower in animals treated with BP plus acetaldehyde than in those
given BP alone. Thus, acetaldehyde did not influence the
carcinogenic effect of BP. Similarly, the carcinogenic effect of
DEN was also not influenced by the treatment with acetaldehyde.
In another study, Feron et al. (1982), studied respiratory
tract tumors in male and female hamsters exposed to high
concentrations of acetaldehyde vapor alone or simultaneously with
either benzo(a)pyrene (BP) or diethylnitrosamine (DEN) were
studied. The animals were exposed 7 hrs/day, 5 days/wk for 52
4-62
-------
weeks to an average concentration of acetaldehyde of 2500 ppm
during the first 9 weeks; 2250 ppm during weeks 10-20; 2000 ppm
during weeks 21-29; 1800 ppm during weeks 30-44; and 1650 ppm
during weeks 45-52. Animals exposed to air or air plus BP or DEN
served as controls. At the end of the exposure period (week 52),
3 animals per sex were taken from groups 1 and 2 for autopsy.
All remaining animals were sacrificed after 81 weeks.
At the end of the exposure period, (i.e., at week 52)
distinct histopathological changes, similar to those of the
previous studies, were found in the nose, trachea, and larynges
of animals exposed to acetaldehyde. No tumors were found in
hamsters killed immediately at the end of the exposure period.
Acetaldehyde-exposed animals which were found dead or
sacrificed at week til exhibited inflammatory, hyperplastic, and
metaplastic changes in the nose and larynx, suggesting a
persistence of those alterations. Tumors were encountered in the
nose (adenoma, adenocarcinoma, anaplastic carcinoma) and the
larynx (papilloma, carcinoma in situ, squamous cell carcinoma,
adeno-squanous carcinoma); animals exposed to acetaldehyde plus
BP or DEN also exhibited tumors of the trachea and the lung. The
neoplastic and nonneoplastic lesions in the larynx were mainly
located either on the true vocal folds or in the most anterior
part of the larynx. None of the animals exposed to air alone
demonstrated nasal or laryngeal tumors nor atypical laryngeal
hyperplasia and metaplasia. The incidence of nasal and laryngeal
tumors in hamsters exposed to acetaldehyde and treated with
4-63
-------
either BP or DEN was similar to that found in hamsters exposed to
acetaldehyde alone. Carcinomas in situ and squamous cell
carcinomas of the larynyes were found after combined treatment,
but were not observed after treatment with either BP or DEN
alone. Based upon these findings, the authors concluded that
•acetaldehyde is an irritant as well as a carcinogen to the nose
and larynx with a weak initiating and a strong 'promoting1
(eoearcinogenic) activity" (sic).
Finally, in a study by Woulersen et al. (1984) male and
female Wistar rats were exposed to 0, 750, 1500, and 3000/1000
ppm of acetaldehyde for 6 hrs/day, 5 days/week for up to 27
months. There was significant nonneoplastic lesions of the
olfactory epithelium at each exposure level. In contrast,
significant nonneoplastic lesions were seen in the respiratory
epithelium only at the highest dose- Statistically significant
numbers of adenocarcinomas were observed at each dose level in
males and females. Squamous cell carcinomas were observed at the
two highest dose levels in males and at the highest dose level in
females. Most of the tumors originated from the olfactory
epithelium. Table 4-12 presents summary tumor response of the
nasal cavity for this study.
4.7* Bpidaaioloqic studies
Since 1981, findings from fourteen new studies have been
made public, with another five studies forthcoming. The five as
yet ongoing studies, are: a case-control study of nasal cancers
by CDC, EPA's case-control study of nasal and pharyngeal cancers,
4-64
-------
Table 4-12.
INHALATION CARCINOGENICITY OP ACBTALOBHTDB
IN RATS — Sumary of Nasal Tunors-f
Incidence of Tuners
Number of Rats
Papillona
Early adenocarcinona
Adenccarc inona
Metastasizing
adenocarcinoma
Carcinoma-in-situ
Early squamous cell
carcinoma
Squamous cell carcinoma
Metastasizifk) squamous
cell carcinona
0
55 (49)
0
0
0
0
0
0
I
0
Males
750
54 (52)
0
2
14*
n
0
0
i
n
Females
1500
55 (53)
0
7*
23**
1
0
1
9*
0
3000
53 (49)
0
2
18**
1
1
3
11**
I
0
54 (50)
0
0
0
0
0
0
0
0
750
55 (48)
1
0
6
0
0
0
0
0
1500
55 (53)
0
2
26**
0
3
0
5
0
3000
55 (53)
0
2
20**
1
5
3
14**
0
+Table taken from Feron, 1984.
Figures in brackets represent the number of animals from which this
tissue was examined microscopically.
In this table, a benign tumor is ignored if a malignant tumor of the same histogenetic
origin is also present in the same tissues.
The absence of a numeral indicates that the lesion specified was not identified
Significance of differences in a pairwise (Fisher's) test between each treatment and control
incidences *P<0.05, **P<0.01.
-------
an SMR study of HCHO-exposed workers by NCI and the Formaldehyde
Institute, a prospective study by Partanen of industrial workers
in Finland, and a cohort study of garment workers by NIOSH.
The new studies released since 1981 have broadened our
knowledge regarding the potential carcinoyenicity of HCHO. The
new epidemiologic studies have contributed stronger evidence and
have supported previous studies which suggested HCHO may be a
human carcinogen. In particular, the Epidemiology Panel of the
Consensus Workshop on Formaldehyde (1984) and the EPA (1984b)
examined a group of studies and concluded that a group of
professionals (anatomists, patholoyists, embalmers, and
undertakers) have a significantly increased mortality from
leukemias and brain neoplasms. These excesses in mortality can
not be attributed to diagnostic bias since these excesses
remained when other professional or like socioeconomic groups
were used as referents (Consensus Workshop on Formaldehyde,
1984). In addition, epidemiologic information in the form of one
study and one abstract report increased nasal cancer risks with
HCHO exposure.
Although all the studies are of cohort or case-control
design, designs essential for judging causality, many of the
studies suffer from limitations that influence their
conclusions. Major drawbacks are: (1) the inability to separate
the contributions of HCHO from the contributions of other
occupational or personal exposures; (2) small sample sizes for
the cohort studies; (3) insufficient follow-up; and (4) low
statistical power.
4-66
-------
One outcome of the design limitations has been low power in
each study to detect small relative risks for rare forms of
cancer.* The ability of a well-conducted study to detect an
increased risk depends upon sample size, years of follow-up,
magnitude of the increase, background incidence of the disease,
desired statistical significance, and type of analysis.
The following text describes the current pool of
epidemiologic data with study designs and findings highlighted.
Table 4-13 identifies these studies. Tables 4-14 through 4-16
present selected power calculations for several of the studies
shown in Table 4-13.
4.7.1 Review of studies
Twenty-three studies of populations who may have been
exposed to HCHO report findings of excess cancers. These studies
are either cohort or case-control designed. Results are
expressed as Standardized Mortality Ratios** or as odds
ratios***. All findings are nonsignificant unless noted
*The power of a study is the ability to detect true association
of the exposure and disease. If a study is likely to claim that
the exposure is not associated with a disease, when in fact an
association existed, it has a low power for detecting that
association.
••Standardized Mortality Ratios (SMR), from cohort studies, are
measures of the extent to which mortality in the exposed cohort
under study compares to the mortality experience among unexposed
persons. An SMR divided by 100 is called a risk ratio.
•**The odds ratio, from a case-control study, gives the extent to
which exposed individuals are represented among the affected
cases more than among the controls to whom they are compared. If
the disease under study is rare, the odds ratio is numerically
very close to its associated SMR, but the causal inference is not
as direct. In addition, an odds ratio obtained from a case-
control study nested within a cohort design can be used to
support conclusions from the cohort study.
4-67
-------
Table 4-13.
fLswta»atal.
at at.
atrt.
tat.
ttrintfi
l
ot
00
•i.
«t at.
*t al.
al.
Cow-font rol
ntwn *t at.
al;
AttartB aairf daw C'"*
CNnleat vofosmi
M.T. aAatane anl
••Ml aNf
alnw ean
In N.c.
I aM •cnraeeii atma
Bw
flnl •InixnttAcil
In
•Ineowcat
In
anl •InaratMt eanerr
In NatUnl
n.ft. Atte •!• am axji
apaclfte wtallt? ntsst
Hilat or
lf le
ntla
ltty
tltr
•offtallcv
Miclonal aM teal mOa
UQ
•••*
•mclflc wwtatlty nine
n.s. aju riBi
U.S.
U.S.
m ant a
19
U.S.
Or f
nn» wto
AnffJBtVB
Ineatlen and paf c
TWO hoaBttat
control anrf ant
pacific
fie
pWpBITC IflVM
la «& «u»
of Inpltal
oolorMtal
for
•nip w mnvfcir*
flolen. rtctw. praatate w twavt eontml*
«trn«) for «M "*« y*=^ «* <*9c0ioal*
control*
!i
-------
Table 4-14
B^aV0w0tav K& aya%
^vine at al. 1477
""SrFiciani
(19*3)
Shannon U 9 ?:>)
patnoioKiata
tfant (19S3) 2026
— oKealcel
vorkara
Taherahaw 867
Aaaociata*^
*™7T9H7)
£jr£r?
Aehaaon (1*<1) 771*
* chanical
•orkan
•
Bl* plant
H«rrtn«ton and 2307
VStec" (l'R2)
"TSIe
petholotlata
Ktrauo at al. 2239
— TTWfl
anatoiiata
Bertazci «t al. 4462
fonaaldUhrae
resin a£a.
Cancer
Tnw
lune
IvBEhat ic fhenatopolet ic
leuVenia /aleukania
proa tat ic
brain
buccal cavity and
noae
line., trachea and bronehua
Itmphonoietic
leukania
raeairatory
lynphoooi et ic
levikania
proa tat ic
brain
raaoiratoTv
Ifuiulijpciietic
proa tat ic
brain/OB
line
Iwohatic
leukania
brain
nuccil cavlrv and
pharmx
noae
Ixng
noae
law.
IfinJuuoietic
UtAareia
brain
raaoiratorv
IWpnODO* Ct He
ladtenia
brain
buccal cavir? and
lire
lane, thaae tu^wra wm ohtalnad bv the approxiMtlon of Baouwnt and Mraalow (1981) and
checked by the aporoximation to the foiaaon.
tad nrben of daatha were not included In paper.
of Poieaon'a Atponential Rinonial Unit (hblina, 1942).
4-69
-------
Table 4-15
Oorxfltional Pouer Calculations for PE* «=tudi_ega
Study Size
Mart* (19*3) 24»0
cnwical
vorkan
Itelrtt* at al.
T1W3J 1132
wd'fewSSl"1*
lilt mm nn ii. i
Ba.»TfffcliUrB
Valrath O**3) 1050
California
•afeaUftttl
ntffTOCT 9t Al* 256
£&nvnt
%09"CCS1S
Italzcll and 4462
cjruffrman
tactile
vorVan
Cancer
TV«
ratslratorv c
IfJivJiuuoietic
pancreas
•rnitourinary ttact
bladder
rwoiratorv
swHat Ic and
latfeonia
@E9BE&£ie
brain arid W?
buecal cavity
4^0 p^ft^/1 IX
•kin
colon
moiratory
Ivocnatlc and
hanatopoietic
Icukonia/aleukenia
vroatatic
brain
buecal cavity
and pharynx
•kin
rarpirator?
A^i^^nat Ic and
twaeeeoictic
lauVonia/aleuko&ia
brain
buccal cavity
•kin
biliary paaaaae* and
Liver
Lug
lvuiu)uuoie£ic
laukenia
brain
buecal cavity and
pharynx
Observed
6
2
y
3
2
76
25
12
15
9
8
8
29
43
19
12
23
9
8
2
11
4
1
3
2
4
106
121
4S
17
18
Rroecte*1
7.5
2.3
1.2
2.5
0.6
70.7
20.6
8.5
16.6
5.8
7.1
.
3.6
20.3
46.0
15.5
f.9
13.1
4.7
6.1
3.4
12.2
6.1
2.4
2.1
0.4
1.1
1.3
117.8
64.2
37.5
18.9
18.0
80
8f
160
120
320
105
121
140
91
156
113
*221
•143
94
123
• 175
• 176
• 193
131
59
90
163
16R
4ft
* 7W
179
* 313
90
• 188
120
90
100
—
Least oet«
with pi
80T
210
350
4*0
320
720
130
1*0
210
170
240
230
280
170
140
170
210
180
270
220
300
180
220
330
380
132n
500
420
.2
.3
.6
.7
.7
ar
240
400
550
370
880
140
_ 17«
240
190
280
250
330
180
150
190
250
200
300
260
340
200
i
440
600
510
^
!4
.8
.8
.8
Oenditlansl en «h* ateetvcd iwfeer of $§sth« •inee riiatrlHition of HO and H. wiint not have a Voisaon distribution
Ottcttinv and Una, 1981).
Thaae nafeati were obtainad ualnt Hollna'a tablet of Polaaon'a BcponantUl BinonUl Uait Ofolina, 1942).
Tirladai only tajrkan with 2. one nonth cxpoaure to fomaldehyde.
4-70
-------
-J
Table 4-16
Rswer Calculations for Case-Control Studies3
Least Relative odds to
Ftudy
Fayerweather et^ aj_. (1982)
rancor deaths
in chemical
workers
Rrinton et^jal. (19R3)
nasal and paranasal
sinus cases in NC and VA
Olsen et al. (J9R4)
nasal cancer
cases in
Denmark
Hayes et al. (1984)
nasal and nasal
sinus cases in
the Netherlands
Size
4R1 cases/
4RI controls
(1:1 match)
160 cases/
290 controls
(1:2 match)
R39 cases/
2465 controls
(1:3 match)
144 cases/
353 controls
(1:2 match)
Cancer Type
lunq, bronchus.
and trachea
Ivmphopoiotic
prostate
hrain
nasal cavity
and sinuses
nasal cavity
and sinuses
nasal cavity
and sinuses
Exposure Ratio = p
formaldehyde:
males workers (20%)
textile workers:
females (17.4%)
formaldehyde:
females (0.1%)
males (4.2%)
textile dust:
females (2.5%)
males (1.9%)
formaldehyde:
males not exposed to
wood dust (6.2%)
nales exposed to
wood dust (50%)
CHds
Ratio
0.74
0.72
3.20
0.45
l.«
2.n
2.R
1.3
0.7
2.n
1.0
detect with
R0%
2.0
3.5
4.4
11.6
2.5
15.0
2.1
2.R
2.4
3.4
5.2
powerh
90
2.2
4.1
5.5
16.8
2.8
18.0
2.3
3.2
2.7
3.7
6.5
Pnwer calculations for Tola
_. (1^80) and Hcmbern et al. (1983) could not be calculated due to the unknown
_
exposure ratio (o ) amonq the controls.
Obtained from the studv by Faverweather ot al. (1982) or was calculated usinq the method in flothman and noire
(1P82) for the studies bv Printon et ^^1983), Olsen et_ al_. (1984), and Hayes ot_aK
-------
otherwise. Ten studies are of chemical or industrial workers and
seven studies of medically-related professions. The medically-
related professions represent formalin exposures such as those
encountered by morticians, embalmers, anatomists, and
pathologists.. This group has other chemical exposures, but by
nature of their professions, formalin is an integral component
and represents the exposure of concern. Lastly, six other case-
control studies examine an occupational etiology of nasal cavity
and sinus cancers. These studies examine the relationship
between nasal cavity and sinus cancer and HCHO exposure or
between these cancers and particular occupational groups where
HCHO has been known to occur.
1. Matanoski (1980) of John Hopkins University examined
mortality patterns of male pathologists in two
professional societies. She observed a 62% excess risk
for multiple myeloma and a 42% excess risk for other
lymphomas for members of the American Association of
Pathologists and Bacteriologists (1900-1929) when
compared to radiologists. When compared to U.S. white
males, Matanoski observed a significant increase in
deaths when she combined the two cancer categories.
Matanoski continued following this cohort until 1974 and
reported a 3-fold significant excess of lymphatic and
multiple myeloma tumors and a 2-fold excess of brain
cancers when compared to age-specific rates for U.S.
white males. Matanoski observed the same pattern of
4-72
-------
significant increases for lymphomas and multiple
myelomas in a second cohort of pathologists belonging to
the Association of Experimental Pathologists. Combining
the two groups without overlap, about 2200 individuals,
Matanoski reported increased mortality from lymphatic
(3-fold excess, pjCO.OOl) and from brain cancer (p£0.05).
2. Harrington and Shannon (1975) of the London School of
Hygiene and Tropical Medicine conducted an SMR analysis
of 2,079 pathologists who were members of the Royal
College of Pathologists or the Pathological Society of
Great Britain during 1955 to 1973. In the period, 156
deaths occurred. The authors reported a significant
excess in mortality from lymphopoietic system cancers
(SMR=200, 8 observed, p<0.05), particularly from
lymphatic and hematopoietic diseases not due to
Hodgkin's disease or leukemia (SMR-353, 6 observed,
p<0.01). Additionally, a nonsignificant increase in
mortality was observed from Hodgkin's disease (SMR=167,
1 observed) for male pathologists in England and Wales.
3. Harrington and Oakes (1982) more recently followed the
Royal College of Pathologists' cohort from 1974 to 1980
and performed an SMR analysis of 2,720 members (2,307
males and 413 females), in which 126 total deaths (110
males, 16 females) occurred. Harrington and Oakes
observed increased mortality in males from cancers of
the brain (SMR=331, 4 observed, p<0.05) and bladder
4-73
-------
(SMR=107, 2 observed), from accidents (SMR=170, 13
observed, p<0.05), and from suicides (SMR=353, 7
observed, p<0.01). Increased mortality from lymphatic
and hematopoietic neoplasms was not reported for male
pathologists (only 2 observed deaths) but was reported
for female pathologists (SMR*370, only 1 observed
death).
All the malignant brain tumors were of the
astrocytoma/glioma cell type. This finding supports a
hypothesis of a common etiologic agent within this
study.
4. Levine et al. (1984) of CUT in an SMR analysis found
excess mortality among Ontario morticians, relative to
U.S. white males, from lymphopoietic cancer (SMR=125, 9
observed), particularly, leukemias/aleukemias (SMR=175,
5 observed), and brain cancers (SMR=118, 3 observed).
None of these malignancies was significantly elevated.
Only cirrhosis of the liver showed a significant excess
(SMR=171, 18 observed). In analyses for latency, Levine
observed increasing SMR's with increasing time since _
first exposed for cancers of the brain, lymphopoietic
system, and leukemia/aleukeroia.
5. stroup et al. (1984) has noted excesses, when compared
to U.S. white males, in mortality due to brain cancers
(SMR=271, 10 observed, p<0.01) and leukemias (SMR=148,
10 observed) in anatomists in her yet-to-be-published
4-74
-------
SMR study. Stroup et al. noted excesses of the cell
types astrocytoma/glioblastoma
-------
ooserved significantly increased mortality from cancer
of the prostate (SMRM31, 4 observed, p<0.05) and
nonsignificantly increased mortality from lymphopoietic
system (SMR=231, 4 observed), including Hodgkin's
disease (SMR-582, 1 observed) and leukemia/aleukemia
(SMR-306, 2 observed), cancers.
Wong's study is limited by a small cohort size, lack of
work histories, and lack of control for such confounding
variables as smoking and multiple exposures. Besides
HCHO, this cohort had potential exposures to other
oxygenated hydrocarbons, benzene, asbestos, and
inorganic and organic pigments. Exposure to benzene is
particularly important since the literature reports a
causal association between leukemia and benzene exposure
(Heath, 1982).
7. Tabershaw Associates (1982) studied the same cohort as
Wong, with 58 men added who had incorrectly been
excluded and with the HCHO-exposed workers identified.
An SMR analysis of the exposed and unexposed cohorts.and
a case-control analysis using randomly-selected controls
among the non-cancer cases were conducted. In the SMR
analysis of 667 HCHO-exposed workers, nonsignificantly
increased mortality from prostatic (SMR=364, 2
observed), brain/CNS (SMR=135, 1 observed), and
lymphopoietic (SMR=152, 3 observed) cancers and from all
accidents (SMR=103, 11 observed) was reported.
4-76
-------
Interestingly, Taoershaw Associates base the b'rain/CNS
conclusion on one observed death, yet the text describes
two observed deaths among men who had 6.7 years and 6.9
years of exposure.
In the case-control analysis, nonsignificantly increased
odds ratios for cancers of the prostate (OR=2.67) and
lymphopoietic system (OR=3.0), and for all neoplasms
(OR=1.2) with 5 to 10 years of HCHO exposure were
reported. No increasing risks were observed with
increasing years of exposure. Tabershaw Associates did
not use an unexposed group as a comparison, but compared
the exposed employees to those with less than 5 years of
exposure.
Friedlander et al. (1983) of Eastman Kodak conducted a
mortality and incidence study of 464 photo processors in
Eastman Kodak's Color Print and Processing
laboratories. These workers had been exposed to HCHO,
along with other photographic chemicals. In the
mortality study, Friedlander et al. compared the death
rates in this cohort to aye-sex-specific death rates in
two other Kodak manufacturing plants. Friedlander et
al. observed excess mortality from cancers of the brain
and CNS (2 observed, Plant 1 comparison - SMR=286; Plant
2 comparison - SMR*667, p<0.05) and digestive organs and
peritoneum (5 observed, SMR=128, for each comparison
group). Nonsignificant excess mortality from cancer of
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the buccal cavity and pharynx was also observed (1
observed, Plant 1 comparison -0.2 expected, Plant 2
comparison - 0.1 expected). From the incidence
analysis, Friedlander et al. also reported the incidence
of brain and CNS cancers increased (2 observed, 0.4
expected, p<0.05) among this group when compared to the
population incidence for upstate New York.
Limitations in the study of Friedlander et al. include
small cohort size, no separation of work exposures,
insufficient length of follow-up, insufficient follow-up
of retired and terminated employees, and no control for
smoking.
9. Acheson (1984a) of MRC Environmental Epidemiology Unit,
Southampton General Hospital, in an ongoing study of six
plants which use or manufacture HCHO, has observed
significant increases in overall mortality (SMR=124, 456
observed) and nonsignificant increases from pharyngeal
(SMR=121, 5 observed), esophageal (SMR=103, 13
observed), respiratory (SMR=102, 236 observed), and lung
(SMR=105, 205 observed) cancers. Additionally, Acheson
found a significant excess of bone cancer and a
significant dose-response relationship for lung cancer
in one plant (BIP), the cohort with the highest
exposure. In a comparison with local controls, the
dose-response relationship, although nonsignificant, was
still observed. Acheson lacks smoking histories for the
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entire conort, and the BIP plant is located in the West
Midlands area, an industrially polluted area with high
referent lung cancer rates. The use of a local
comparison may have overestimated the number of expected
lung cancer deaths. In a subsequent analysis of the
mortality data for lung cancer among individuals
employed at this plant, Acheson et al. (1984b) observed
that the risks for lung cancer did not increase with
duration of exposure, length of follow-up, or cumulative
doses.
10. Marsh (1983) of the University of Pittsburgh conducted
an SMR analysis and a case-control study nested within
the cohort of a Monsanto chemical plant. This plant
produced plastics and workers had potential exposures to
HCHO, vinyl chloride, styrene, and cellulose acetate.
Marsh compared the mortality experience of all workers
to the white male populations of the U.S., of
Massachusetts, and of Hampden County, the county from
which the workforce was drawn. In the SMR study, the
cohort consisted of 2,490 male workers with a minimum of
one year employment. Among the 2,490 workers, 591
deaths were identified by the company or by death
certificate searches. Marsh reported nonsignificantly
increased mortality due to all neoplasms (SMR=107, 127
observed). Among all neoplasms, excess mortality was
observed from cancer of the buccal cavity and pharynx
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(SMR=155, 6 observed), digestive organs and peritoneum
(SMR=126, 44 observed), prostate (SMR=178, 14 observed) ,
bladder (SMR=135, 5 observed ), genitourinary tract
(SHR-169, 26 observed, p<0.05), Hodgkin's disease
(SMR=118, 2 observed), and all other lymphopoietic
tissue (SMR=153, 4 observed). No relationship was
observed between genitourinary system neoplasms and
length of employment.
In the matched case-control study based on the cancer
deaths, Marsh presented odds ratios for digestive
system, rectal, genitourinary, and prostatic cancers and
21 occupational exposure categories. Two of the 21
categories had pertinent exposure to HCHO either as a
chemical (resin production) or in a product (resins
processing)e Marsh observed nonsignificantly increased
odds ratios for digestive system cancer in the resins
processing category (OR=1.83) and for rectal cancer in
both categories (resins production, OR=3.75; resins
processing, OR=2.00). All cases in the occupational
categories had from 1 month to 5 years exposure and
increasing risk was not observed with increasing
duration of exposure*
11. Fayerweather et al. (1982) of DuPont showed elevated
odds ratios, after a 15 year latency, for cancers of the
prostate (OR=4.8, 8 cases), lymphopoietic system
(OR-1.91, 6 cases), bone (OR=1.25, 3 cases), and bladder
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(OR=7.0, 6 cases) among workers eligible for pension who
were exposed to HCHO five or more years. Additionally*
these elevations were not significant upon adjusting for
a variety of coneommitant variables. Fayerweather et
al. did not follow those employees ineligible for
pension or those who had transferred, potentially
comprising 15 to 20% of the work group. Thus, these
analyses were performed on an incomplete cohort and the
results may be biased.
12. Brinton et al. (1984a) of NCI conducted a case-control
study for cancer of the nasal cavity and sinuses. They
observed nonsignificantly increased odds ratios among
males employed in the leather or shoe, chemical
manufacturing, and carpentry industries and for
exposures to chromium/chromates, nickel, and
insecticides/pesticides/herbicides. Among females,
increased odds ratios were observed with employment in
the textile/clothing/hosiery and paper/pulp mill
industries and for exposures to mineral oils and other
mineral/chemical gases. None of the increased odds
ratios was significant in the presence of control for
confounding variables. Brinton et al. additionally
assessed reported occupational HCHO exposure and found
an odds ratio less than 1.0. This ratio was unstable,
based on only one male and one female.
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To examine the relationship between employment in the
textile and apparel industries with the risk of nasal
cancer, Br inton _e_t _al_. (1984t>) further analyzed the
data from their previously published case-control study
(1984a). The industries included textile and cotton
mills, apparel manufacturing, and hosiery. Brinton et
al» found an elevated risk of nasal cancers associated
with employment in the textile or apparel industries,
but the increased relative risk was found only among
female workers. When histologic types of nasal cancer
were evaluated, both males and females were found to be
at increased risk of nasal adenocarcinoma, with further
enhancement of risks for those experiencing dusty work
conditions. The authors stated that this study provides
further evidence of an association between employment in
the textile industry and risk of nasal cancer.
13. Tola et al. (1980) of the Institute of Occupational
Health, Finland, conducted a case-control study for
cancer of the nose and paranasal sinuses. Forty-five
cases were collected from the Finnish Cancer Registry
between 1970 and 1973 and were aye-sex matched to non-
respiratory cancer controls.
Analyses examining an occupational etiology showed no
single occupation being more common among the cases than
among the controls, but leisure time knitting and sewing
was s'ignificantly more common among female cases than
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fiL-nong female controls (OR=4.8, 19 cases). Other factors
significantly associated with the cases were histories
of serious nasal trauma, chronic rhinitis, and
sinusitis. Smoking was not significantly associated
with nasal cavity and sinus cancer.
14. Hernberg et al. (1983) of the Institute of Occupational
Health, Finland, conducted, with participation from
Denmark and Sweden, a collaborative case-control study
of nasal and sinonasal cancer and its possible
occupational etiology. One hundred seventy cases
diagnosed between 1977 and 1980 and reported to the
prospective cancer registries were selected. Each case
was sex-country-age at diagnosis matched with colorectal
cancer controls.
Elevated odds ratios were observed among cabinetmakers
(OR=9.0) and mechanical engineering shop workers
(OR-2.13). Analysis for exposures showed elevated risk
with hardwood dust (OR=1.7)*, softwood dust (OR=3.4,
p<0.05)* hardwood and softwood dust (OR=6.7, p<0.05)*,
welding-flame cutting-soldering (OR=2.0, 17:6,
p<0.05)**, chromium (OR«2.7, 16:6, p<0.05)**, nickel
(OR-2.4, 12:5)**, electroplating (OR«1.5, 9:6)**, and
paint-lacquer (OR=3.0, 18 cases). HCHO exposures may
occur in this last category. However, wood dust
exposure is common and confounds the observed elevation.
*Adjusted for smoking.
**Odds ratio based on discordant pairs, discordant paris noted,
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15. Stayner et al. (1964) of N10SH conducted a PMR study of
256 deaths among garment workers. Stayner et al.
identified these deaths from a death benefit fund. In
this cohort, which represented three plants in two
different states, Stayner et al. observed significantly
elevated mortality from buccal cavity (PMR=750, 3
observed), biliary passages and liver (PMR=313, 4
observed), and other lymphatic and hematopoietic site
(PMR=400, 4 observed) cancers. In analyses examining
only the cancer deaths, buccal cavity (PCMR=682) and
other lymphatic and hematopoietic site (PCMR=342)
cancers remained significantly elevated. Additionally,
those workers with both latency and duration of exposure
of 10 years or greater showed significantly elevated
mortality from all malignancies (PMR=137, 51 observed),
buccal cavity (PMR=925, 2 observed), biliary passages
and liver (PMR=467, 3 observed), and all lymphatic/
hematopoietic sites (PMR=283,8 observed), particularly
other lymphatic and hematopoietic (PMR=761, 4 observed)
-- cancers. -_.... _.....
Nonsignificant elevations in mortality were reported for
liver not specified (PMR-426, 2 observed), skin
(PMR-179, 2 observed), and all lymphatic and
hematopoietic sites (PMR=163, 10 observed), including
leukemia (PMR=400, 4 observed).
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16. Walrath and Fraumeni (1983) of NCI conducted a py.R study
of 1,132 funeral directors or embalmers licensed in New
York. In this cohort, Walrath and Fraumeni observed
significantly elevated mortality from skin (PMR=221, 8
observed) and colon (PMR=143, 29 observed) neoplasms.
Nonsignificant elevations were observed for cancer of
the buccal cavity and pharynx (PMR=113, 8 observed),
digestive system (PMR«104, 68 observed), particularly
liver (PMR=106, 5 observed) and pancreas (SMR=105, 13
observed), respiratory system (PMR-105, 74 observed),
brain/CNS (PMR=156, 9 observed), kidney (PMR=150, 8
observed), and lymphatic/hematopoietic system (PMR=121,
25 observed). Among those licensed as embalmers only,
Walrath and Fraumeni observed increases in mortality
from buccal cavity and pharyngeal (PMR=201, 7 observed),
skin (PMR=326, 5 observed, p<0.05), kidney (PMR=247, 6
observed, p<0.05) and brain/CNS (PMR=234, 6 observed,
p<0.05) cancers. In the analysis for latency, Walrath
and Fraumeni observed, for the entire cohort, increasing
PMRs for skin (significantly so) and brain/CNS neoplasms
for increasing tine since first exposed.
17. Nalrath (1983) conducted another PMR analysis of 1050
embalmers in California and reported similar findings as
those in the N.Y. cohort. Walrath observed
significantly increased mortality from neoplasms of the
brain (PMR=193, 9 observed), leukemia (PMR=175, 12
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observed), and prostate (PMR=176, 23 observed).
Nonsignificant increases were reported for
lymphatic/hematopoietic system (PMR=123, 19 observed)
and buccal cavity and pharyhgeal (PMR=131, 8 observed)
cancers.
18. Marsh (1983) of the University of Pittsburgh conducted a
PMR analysis of HCHO-exposed workers at the Monsanto
plant described previously. Marsh found 136 death among
male workers with exposure of one month or greater in a
"formaldehyde related plant area". Marsh compared their
mortality experience to U.S. male, age-race adjusted,
proportional mortality data.
In the HCHO-exposed white males, Marsh observed
increased (not statistically significant) mortality from
cancers of the genitourinary system (PMR=121, 3
observed), including the bladder (PMR=330, 2 observed)
and of the digestive organs and peritoneum (PMR=127, 8
observed), particularly the pancreas (PMR=160, 2
observed). In the non-white exposed workers, Marsh does
not report any increases in neoplastic deaths, but
observed increases among the non-neoplastic deaths,
particularly diseases of the circulatory system
(PMR=102, 7 observed), digestive system (PMR=158, 2
observed), and accidents (PMR-106, 2 observed). In the
unexposed group, white males exhibited increased
mortality from genitourinary tract cancers (PMR=192, 22
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observed) and digestive organs and peritoneal cancers
(PMR=130, 33 observed). Non-white unexposed males
exhibited increased mortality from all malignant
neoplasms (PMR=251, 5 observed), particularly in the
categories "all other malignant neoplasms" (PMR*882, 3
observed, p<0.01), diseases of the nervous system
(PMR=155, 2 observed)) and circulatory disease (not
including arteriosclerotic heart disease) (PMR-207, 3
observed).
Since Marsh published this study, Peter Infante of OS HA
has found one cancer of the nasal sinus and one
nasopharyngeal cancer. Both men died three years after
Marsh's follow-up period. The worker who later died of
cancer of the nasopharynx was a member of Marsh's
cohort, but had been counted as living since he had not
died at that time.
19. An overlapping study was conducted by Liebling et al.
(1984) (as reported by OSHA, 1984). Liebling et al.
identified 24 male workers who died between January 1,
1976 and December 31, 1980 through union records,
reports of former coworkers, and a systematic review of
obituaries in local newspapers. Work histories were
obtained from seniority lists.
Proportionate mortality ratios were calculated to
examine cause-specific mortality using the age, sex;
race and cause-specific mortality proportions of the
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U.S. and county in which the plant is located. To
adjust for the healthy worker effect, age, sex, and
race-standardized PCMRs based on county comparisons were
also calculated. Deaths among eighteen white and six
black males with Known HCHO exposure were identified.
Race-age-sex adjusted PMRs were significantly elevated
for cancer of the colon based on U.S., county, and
county cancer mortality proportions (PMR = 702, 424,
333, pjc^ 0.05), as were PMRs for the cateogry buccal and
pharyngeal cancer (PMR = 870, 952, 833, p^O.05).
Liebling et al. stated that the occurrence of a
significant increase in proportionate mortality from
buccal and pharyngeal cancer in this investigation is in
accord with the type of cancer found in HCHO-exposed
rodents. Furthermore, the authors postulated that
besides nasopharyngeal cancer, an association between
HCHO exposure and cancer of the buccal cavity and
pharynx in humans is biologically feasible since humans
breathe through both the nose and nouth, while rats and
mice are obligatory nose-breathers. Like many "other
studies, this study is limited by the inability to
completely separate HCHO exposure from exposure to other
chemicals.
20. Olsen et al. (1984) of the Danish Cancer Registry
conducted a case-cohort study of nasal cancers. This
study examined 839 cancer registry cases (560 males, 279
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females), diagnosed between the years 197C-1S52, who
were matched with 2,467 controls with cancer of the
colon, rectum, prostate, and breast on age-sex-year of
diagnosis. The researchers used a nationwide data
linkage system which has linked cancer cases and
previous employment. Occupational histories came from
the National Supplementary Pension fund, established in
1964, and the Central Population Registry. Use of these
national data sets eliminated tne potential for recall
bias since cases and controls were not interviewed.
In this case-control study, Olsen et al. tested for
associations between HCHO, wood dust, paint-laquer-glue,
and metal exposure and sino-nasal cancers.
Significantly increased risks were found for nasal
cavity cancer for exposure to HCHO (OR=2.8), wood dust
(OR=2.5), and paint-lacquer-glue (OR=2.1). Exposure to
both wood dust and HCHO can occur simultaneously, and
Olsen et al. performed a stratified analysis which
controlled for wood dust exposure. In this analysis,
the elevated risk with HCHO exposure was reduced to 1.6
and became nonsignificant. In this stratified analysis,
both HCHO and wood dust exposure together resulted in an
additive risk (OR=4.1, g
-------
Conference on Epidemiology and Occupational Health in
Dublin, Ireland. The Hayes et al. study identified
factors associated with 144 cases of nasal and sino-
nasal neoplasms diagnosed between 1978 and 1981. Living
and deceased population controls were used as the
comparison group, but Hayes et al. did not identify the
criteria for control selection. Hayes et al. observed
associations between male adenocarcinoma cases and work
in furniture, making (OR=132) and joinery (OR=21). In
addition, Hayes et al. noted significantly increased
risks between nonadenocarcinomas and paint (OR-4.1),
benzene (OR=2.3), and HCHO (OR-2.4) exposure.
In analyses which controlled for simultaneous wood-dust
and HCHO exposures, Hayes et al. observed a
nonsignificantly elevated risk for exposure to only HCHO
(OR=2.8). Hayes et al. did not show, however, an
addition of risk for both HCHO and wood-dust exposures
like Olsen et al. reported.
22. Bertazzi et al. (1984) of the Institute of Occupational
Health, University of Milan presented at the above
conference findings of a cohort study of HCHO resin
manufacturing workers. The mortality experience of
1,332 male employees who had worked six (6) months or
more between 1959 and 1980 was compared to the expected
number of deaths using national and local rates.
Bertazzi et al. noted that ambient monitoring of many
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work areas were above the Threshold Liir.it Value (value
not given), but the researchers do not identify when
these samples were obtained or where the monitors were
located.
For the entire cohort, Bertazzi et al. observed
significantly increased mortality for lung cancer when
both national (18 observed, 7.6 expected) and local (9.7
expected) rates were used as the referent. Mortality
from digestive neoplasms and lymphopoeitic neoplasms was
nonsignificantly elevated.
Bertazzi et al. compared the mortality of HCHO exposed
workers to non-exposed workers. In this analysis, the
increased mortality from lymphatic and hematopoietic
system and from digestive neoplasms was observed only
among the HCHO exposed. Elevated mortality was observed
in both the HCHO exposed and nonexposed groups.
23. Delzell and Grufferman (1983) of Duke University
examined the mortality experience of 4,462 deaths
between 1976-1978 of white female textile workes.
Deaths and occupation as recorded on the death
certificates were identified from state computer
files. In this study, textile worker occupational code
included workers in industries that manufactured textile
mill products, apparel, or other fabricated textile
products. Delzell et al. observed significant excesses
in mortality from cancer of the larynx (PMR=280, 5
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ooserved), connective tissue (PMR = 260, 10 observed),
cervix (PMR=210, 59 observed), other unspecified genital
organs (PMR=270, 16 observed), and non-Hodgkin1s
lyrophoma (PMR=170, 51 observed), and all lymphopoietic
sites (ICDA 200-207) (PMR=188, 121 observed), mortality
from Hodgkin's disease (PMR- 111, 8 observed) and
leukemia (PMR*12Q, 45 observed). The elevated mortality
from all lymphopoietic sites and from specific
lymphopoietic sites are particularly interesting since
HCHO, along with other chemicals, may comprise exposures
in textile mills. EPA used an exposure level of 0.10
ppm (personal sample) and 0.42 ppm (area sample) in its
Quantitative Risk Assessment for Formaldehyde (EPA,
1984). Since this study was unable to identify
individual exposures, we do not know if any or all
deaths may have had previous HCHO exposure.
4.7.2. Conclusion
The epidemiologic literature report, for the first time, a
significant association between nasal cancer and HCHO. This
observation was confounded due to wood dust exposures, but when
the analyses controlled for wood dust, the risk remained elevated
(nonsignificantly). The association between nasal cancer and
HCHO nay be further supported by the report of Hayes et al.
(1984). A critical review of the Hayes et al. study needs to be
done and EPA epidemiologists have requested, but have not
received, a copy of the paper. In addition, the significant
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excesses in leukemia and brain cancer mortality among anatomists,
pathologists, and embalmers are also important. These observed
excesses can not be explained by diagnostic bias or socioeconomic
factors.
Low power is a characteristic of several studies (Tables
4-14 through 4-16). Selecting lymphatic and hematopoietic cancer
as an example, Table 4-14 shows that Levine et al. (1983) could
detect, with 80% power, a relative risk of 2.2 or greater and
with 90% power, a relative risk of 2.5 or greater. Insufficient
follow-up and small sample sizes contribute doubly to low power
through insufficient person-years and through cancers not yet
having appeared. Thus, absence of significant elevations in
either brain cancer, lymphopoietic cancer, or leukemia in
individual studies should not override the findings in Matanoski,
Stroup et al., Walrath and Fraumeni, Walrath, Harrington and
Oakes, Harrington and Shannon, Tabershaw Associates, Stayner et
al., Olsen et al., and Hayes et al.
Secondly, the discussed studies lack historical exposure
estimates and this cannot resolve the possible contributions of
HCHO from other chemicals. Leukemias and brain cancers have been
associated with other occupational groups. These include
chemists, rubber workers, and oil refinery/petrochemical workers
(Heath, 1982 and Schoenberg, 1982). These occupational groups
are exposed to solvents, benzene, and other organic chemicals.
These exposures may be like those of the medically-related
professions and the chemical manufacturing workers.
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Additionally/ nasal cancer and lymphopoietic cancers have been
associated with textile workers but we do not know if HCHO off-
gasses, dusty/poor sanitary conditions, or yet a third factor
could be the etiologic agent.
In summary, the epidemiologic data made public since the
4(f) decision add more weight to the evidence that HCHO may be a
human carcinogen* Excess mortality from leukemias and brain
cancers have been noted in a group of professionals who use
formalin. Additionally, through case-control methods, an
association between nasal cancer and HCHO has been observed in
one study and a suspect association has been reported in an
abstract of another study. At this time, there is limited
evidence that HCHO may be a human carcinogen.
4.8. tteight-of-Evidence
4.8.1. Assessment of Human Evidence
EPA has determined, based upon its proposed cancer risk
assessment guidelines, that there is limited evidence that HCHO
may be a human carcinogen.
As discussed in the Epidemiology section, the literature
reports (Hayes et al. , 1984; and Olsen et al., 1984), a
significant association between nasal cancer and HCHO. However,
these observations were confounded due to wood dust exposures.
When the analyses controlled for wood dust, the risk remained
numerically elevated but lost its statistical significant (pO.
05). The significant excesses in leukemia and brain cancer
mortality among anatomists, pathologists, and embalmers are also
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important. These observed excesses cannot be explained by
diagnostic bias or socioeconomic factors. The determination that
there is limited human evidence is based on an examination of the
technical merits (power, follow-up, confounding, etc.) of the
available studies and the association of HCHO wood dust and nasal
cancer and the excess mortality seen in professional groups from
leukemias and brain cancers.
4.8.2. Assessment of Animal Studies
The principal evidence indicating that HCHO is able to
elicit a carcinogenic response in animals are the studies by CUT
(1981), Albert et al. (1982) and Tobe et al. (1985). In the CUT
(1981) study, statistically significant numbers of squamous cell
carcinomas of the nasal cavity of Fischer 344 male and female
rats were seen. The CUT (1981) study was a well conducted,
multidose inhalation study. In addition, while not statistically
significant, a small number of squamous cell carcinomas were seen
in male mice. Because this type of nasal lesion is rare in mice,
these data must be considered biologically significant.
Supporting the findings above, are the results of the Albert et
al. (1982) studies in which statistically significant numbers of
squamous cell carcinomas were found in Sprague-Dawley male rats
and the results of Tobe et al. (1985) study in which significant
numbers of squamous cell carcinomas were also found but in
Fischer 344 male rats.
Additional support is provided by studies by Dalbey et al.
(1982) in which HCHO increased the production of tumors caused by
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a known animal carcinogen; Meuller et al. (1978) in which a
•solution of formalin produced lesions in the oral mucosa of
rabbits which showed histological features of carcinoma in situ;
and studies by Watanabe et al. (1954, 1955) in which injections
of formalin and hexamethyenetetramine produced injection site
sarcomas and one adenoma.
HCHO is omtayenic in numerous test systems, and it is able
to transform a number of cell lines. In addition, HCHO has been
shown to be able to form adducts with DNA in both in vivo and in
vitro tests (Consensus Workshop on Formaldehyde, 1984). Its
ability to interfere with DNA repair mechanisms has also been
demonstrated. However, evidence demonstrating HCHO's mutagenic
potential in in vivo tests is lacking (IRMC Report on Systemic
Effects, 1984b). The literature reports conflicting data
concerning chromosomal effects in humans. However, the weight of
this data indicates little if any potential for these effects in
the workplace, but this judgement must be tempered by the
limitations of the studies.
Although HCHO's acute effects do not demonstrate its
carcinogenicity, they do help explain differences in species
response, and the severity of the carcinogenic response in the
animal studies, HCHO's acute effects may be factor in the
promotion of its carcinogenic potential at concentrations greater
than 1 ppm in rats and possibly in humans.
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HCHO is not the only aldehyde that is carcinogenic in
animals. Acetaldehyde, the closest aldehyde to HCHO in
structure, is carcinogenic in hamsters and rats, causing cancers
in the nose and trachea of the former, and nasal cancers in the
latter, in addition, other aldehydes such as glycidaldehyde and
malondialdehyde have been shown to be carcinogenic.
Finally, factors such as HCHO's rapid metabolism, the
protective action of the raucous layer* respiratory response to
sensory irritants, and species differences have been discussed in
the HCHO literature as defense mechanisms that may indicate a
threshold (at exposures of about 1 ppm) or may substantially
reduce cancer risks from HCHO exposure.
In EPA's judgment, the body of metabolism data do not
demonstrate a threshold for HCHO's carcinogenicity. Although the
data indicate that HCHO is rapidly metabolized in in vivo and in
vitro studies, and that transport to sites distant from the point
of contact is unlikely, the fact remains that HCHO-DNA
interaction is indicated for exposures below 2 ppm. In addition,
the finding of benign tumors in the Kern et al (1983) study at 2
ppm is consistent with a conclusion that HCHO is not metabolized
(removed) before it can interact with nuclear material. (The
assumption is that there is a dose-response below 2 ppm for
benign tumors and not a threshold just below 2 ppm.) Whether
this pattern of interaction with DNA is linear or non-linear has
not been unequivocally determined. However, as discussed in
another section, a reasonable interpretation of the data on DNA
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adducts by EPA indicates linearity in the exposure range
tested. In addition, it is impossible to say at this time, if
ever, what level of rapidity of riCHO metabolism versus increases
in exposure is an indicator of a threshold.
The defensive role of the mucous layer in preventing
exposure of target cells to HCHO has been extensively
discussed. However? the data indicate that the mucous layer has
not been shown to be able to trap and remove significant amounts
of HCHO at the levels tested in Casanova-Schmitz et'al. (1984).
In fact, the data indicate that a constant proportion of HCHO
reaches the underlying cells. While this does not imply that the
mucous layer offers no protection, it does not support a
threshold hypothesis.
The effect of sensory irritants on the respiratory rates of
some laboratory animals is well known. Such a response
apparently contributes to the minimal neoplastic response seen in
mice. This is an important factor when interpreting inhalation
studies and in determining the dose actually received. While a
reduction in respiratory rate protects the animal by reducing the
amount of the irritant irihaled, J.t plays no defensive role_ below
exposures which fail to elicit the response. However, it is a
factor in the generation of risk estimates since the nominal dose
levels used for statistical purposes may need to be changed to
reflect this effect.
Another factor that bears on the possible carcinogenicity of
HCHO, is the different responses seen in laboratory animals to
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HCHO. HCHO have Deen studied in rats, mice, hamsters, and
monkeys by inhalation. In rats a highly statistically
significant response was obtained in two strains. In mice only
males of one strain showed a marginal response, while hamsters
and monkeys showed no neoplastic response. While mice did not
show a statistically significant response, the response was
biologically significant given the rarity of nasal tumors in
mice. However, the studies of respiratory response to sensory
irritants indicate that when dose received is adjusted for
reductions in respiratory rate, rats and mice appear to respond
similarly. The cancer test data on hamsters are negative.
However, the possibility exists that they may be responding to a
sensory irritant in the same manner as mice. The study using
monkeys indicates that, at least for nonneoplastic lesions
(squamous metaplasia), rats and monkeys respond similarly.
In addition, as a matter of policy EPA chooses to use the
most sensitive species to predict human risk. Even though
studies on the hamster show no observed tumors, the studies do
not negate the rat data and there are no data to show that the
hamster's response to HCHO exposure is more representative of the
human response than is the rat's. EPA's position is supported by
the Risk Assessment Panel of the Workshop (1984), which stated
that there are "no indications that the response by humans would
be different than that exhibited by rats, mainly due to the lack
of experimental data pertaining to this issue. Qualitatively,
the metabolic pathways of HCHO in rats and humans are similar.
4-99
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The sites of greatest exposure may differ, since rats are obliged
to breathe solely through the nose and humans may also breathe
orally. Again, no information exists demonstrating that the
response would be quantitatively different as a result of
differences in distribution of the inhaled dose."
In conclusion, based on EPA's proposed Cancer Risk
Assessment Guidelines there is sufficient evidence that HCHO is
an animal carcinogen.
4.8.3. Categorization of Overall Evidence
In conducting risk assessments of suspect carcinogens, EPA
generally evaluates the overall weight-of-evidence including both
primary and secondary evidence of carcinogenicity. As specified
in the draft EPA Guidelines for Health Assessment of Suspect
Carcinogens (EPA, I984a), primary evidence derives from long-term
animal studies, and epidemiological data insofar as this is
available. Secondary, or supplemental, evidence includes
structure-activity relationships, the results of short-term
tests, pharmacokinetic studies, comparative metabolism studies,
and other toxicological responses which may be relevant (EPA,
19>84).
In the process of categorizing HCHO, two lines of evidence
were assessed, one of which is an assessment of studies of humans
and the other is the assessment of evidence from studies in
animals. The results from each assessment are then combined to
characterize the overall evidence of carcinoyenicity. The draft
EPA Guidelines also suggest that quantitative risk numbers be
4-100
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coupled with EPA classifiat ions of qualitative weight of
evidence.
Consequently, based on the determination that there is
sufficient evidence that HCHO is an animal carcinogen and the
determination that there is limited human evidence, HCHO can be
classified under the draft guidelines as a Group Bl-Probable
Human Carcinogen.
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5. HAZARD OF NONCARCINOGENIC EFFECTS
5.1. HCHO-Related Effects of the Eves and Respiratory System*
Irritation of the eyes and mucous membranes is the principal
effect of low concentrations of HCHO observed in humans. Human
responses to airborne HCHO at various concentrations are
summarized in Table 5-1. Table 5*1 shows a wide range in HCHO
concentrations reported to cause specific health and sensory
•ffects. At concentrations below 0.05 ppn none of the effects
listed have been reported.
Table 5-1.
REPORTED HEALTH EFFECTS OP FORMALDEHYDE
AT VARIOUS CONCENTRATIONS
Approximate HCHO
Health Effects Reported Concentration, ppm*
None reported 0-0.5
Odor threshold 0.05-1.0
Eye irritation 0.01-2.0**
Upper airway irritation 0.10-25
Lower airway and pulmonary 5-30
effects
Pulmonary edema, inflammation, 50-100
pneumonia
Death 100+
•Range of thresholds for effect listed.
**The low concentration (0.01) was observed in the presence of
other pollutants that may have been acting synergistically.
•Unless otherwise cited, from NRC (1981)
5-1
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Most persons can perceive the odor of HCHO at about 1 ppm,
but some persons can detect it as low as 0.05 ppm. Eye
irritation has been reported at concentrations as low as 0.05
ppra. At concentrations at or above 1 ppro, nose, throat, and
bronchial irritation have been noted. Such irritation was nearly
uniformly reported by persons when the concentration reached 5
ppra, ECHO concentrations exceeding 50 ppm cause severe pulmonary
reactions, including pneumonia, bronchial inflammation, pulmonary
edema, and sometimes result in death.
Table 5-1 shows the variability and overlap of thresholds
for responses among subjects. Although the severity of an effect
in a person increases with increasing concentration and duration
of exposure, a dose-response for an individual, the thresholds
for the effects vary in the population as Table 5-1
illustrates? The problem is to determine population dose-
response relationships. Tolerance to olfactory, ocular, or upper
respiratory tract irritation occurs in some persons. Factors
such as smoking habits, socioeconomic status, preexisting
disease, and interactions with other pollutants and aerosols are
expected to modify these responses.
5.1.1- !yj,
& common complaint of persons exposed to HCHO vapor is eye
irritation. Some persons can detect HCHO at 0.01 ppm, but it
produces a more definable sensation of eye irritation at 0.05-0.5
ppm. Marked .irritation with watering of the eyes occurs at a
concentration of 20 ppn in air. Permanent eye damage from HCHO
5-2
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•
vapor at low concentration is thought not to occur because people
close their eyes to avoid discomfort. Increased Dlink rates are
noted at concentrations of 0.3-0.5 ppm in persons studied in
chambers. Blink rate, although used as an objective measure of
eye irritation, appears variable for any given subject. The
irritant effects of HCHO seem to be accentuated when it is mixed
with other gases. In •nog-chamber testa human subjects tested
could readily detect and react to HCHO at as low as 0.01 pptn.
Accidental splash exposures of human eyes to aqueous
solutions of HCHO have resulted in a wide variety of injuries,
depending on concentration and treatment. These range from
discomfort and minor, transient injury to delayed, but permanent,
corneal opacity and loss of vision.
In summary, human eyes are very sensitive to HCHO, detecting
atmospheric concentrations of 0.01 ppm in some cases (when mixed
with other pollutants) and producing a sensation of irritation at
0.05-0.5 ppm. Tolerance to eye irritation is reported to
occur. Lacrimation is produced at 20 ppm, but damage is
prevented by closing the eyes in response to discomfort. Aqueous
solutions of HCHO accidentally splashed into the eyes must be
immediately flushed with water to prevent serious injury, such as
lid and conjunctival edema, corneal opacity, and loss of vision.
5.1.2. Olfactory System
The odor threshold of HCHO is usually around 1 ppm, but nay
be as low as 0.05 ppm for a small percent of the population.
General olfactory fatigue with associated increases in olfactory
5-3
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thresholds for rosemary, thymol, camphor, and tar has been
reported among plywood and particleboard workers and is thought
to be associated with HCHO exposure.
5.1.3. Upper Airway Irritation (Nose and Throat)
Symptoms of upper airway irritation include the feeling of a
dry or sore throat, tingling sensation of the nose, and are
usually associated with secretion of tears and pain in the
eyes. Irritation occurs over a. vide range of concentrations,
usually beginning at approximately 0.1 pptr., but is reported more
frequently at 1-11 ppm (see Table 5-1). Tolerance to eye and
upper airway irritation may occur after 1-2 hours of exposure.
However, even if tolerance develops, the irritation symptoms can
return after a 1- to 2-hour interruption of exposure.
Finally, examinations of the nose and throat reveal chronic
changes that are more severe in persons exposed to the higher
concentrations HCHO. Exposure to HCHO can cause alterations in
the nasal defense mechanisms'kthat include a' decrease in
-'." "-'•-•-'•..'• '-'V-.--:-.-- •••»•• -• •-!8#>-*'*>"
mucociliary clearance and a loss of olfactory sensitivity.
~ '* ,-^f. . r
5.1.4. Lower Airway and Pulmonary Effects "~
• • • • e
Lower airway irritation which is characterized by cough,
chest tightness, and wheezing is reported often in people exposed
to ECHO at 5-30 ppm.
Plyraonary edema and pneunonitis could result from very high
HCHO concentrations, 50-100 ppm. It is not known what
concentrations/durations are lethal to humans, but concentrations
exceeding 100 ppm would probably be extremely hazardous to most
5-4
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exceeding 100 ppm would probably be extremely hazardous to most
and might be fatal in sensitive persons.
5.1.5. Astnma
HCHO has been shown to cause bronchial asthmalike symptoms
in humans. Although asthmatic attacks nay in some cases be due
specifically to HCHO sensitization or allergy, HCHO seems to act
•ore commonly as a direct airway irritant in persons who have
bronchial asthmatic attacks from other causes. Persons with
bronchial asthma respond to numerous agents, such as exogenous
irritants and allergens, respiratory infections, cold air, smoke,
dust, and stress. The asthmatic person seems to represent an
extreme on the scale of respiratory sensitivity to inhaled
irritants.
Diagnosis of immune sensitization has been based upon
knowledge that individuals were exposed to HCHO before onset of
symptoms, and on disease symptoms and the spirometric pattern of
changes in respiratory function upon bronchial provocation by
inhalation challenge with HCHO. Although the production of
specific Immunoglobulin Type E (IgE) antibody has been
demonstrated to other chemicals (e.g., trimellitic anhydride, and
phthalic anhydride), IgE antibody has not been shown to HCHO.
Furthermore, respiratory aensitization with HCHO has not been
demonstrated with animals (this nay not be critical because there
is not a veil recognized model for "asthma") nor in some human
studies in which patients who complained of respiratory illness
did not respond positively to bronchial challenge testing with
HCHO gas.
5-5
-------
Definite conclusions on whether immune sensitization from
HCHO plays a role in asthma and other respiratory disease must
•wait the demonstration of the production of specific igE or
other specific immunological reactions (e.g. specific immune
complexes, activation of the complement cascade, cell-mediated
reactions in hypersensitivity pneumonitis). Studies are underway
to answer some of these points.
5.1.6. Summary
A number of lower airway and pulmonary effects may occur *
from HCHO exposure. Thresholds have not been established for the
irritant effects of inhaled HCHO. However, within the range of
0.1 to 3 ppm, roost people experience irritation of the eyes,
nose, and throat. In most healthy persons exposed to HCHO,
concentrations greater than 5 ppm will cause cough and possibly a
feeling of chest tightness. In some susceptible persons,
concentrations below 5 ppm can cause these symptoms, including
wheezing. In persons with bronchial asthma, the irritation
caused by HCHO may precipitate an acute asthmatic attack,
possibly at concentrations below 5 ppm. Sufficiently well-
controlled studies are not available to definitively establish
the development of respiratory tract allergy to HCHO as a gas.
In concentrations greater than 50 ppm, severe lower respiratory
tract effects can occur, with involvement not only of the airways
tout also of alveolar tissue. Acute injury of this type includes
pneumonia and pulmonary edema.
5-6
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5.2. Irritation/Sensitization—Dermal and Systemic
In reviewing any analysis of respiratory effects, it is
important to remember that irritation and sensitization are two
distinct physiologic responses. Irritation is a purely local,
immediate response resulting from a chemical reaction between
HCHO and the epithelial lining of the airways. The irritant
response will resolve with cessation of exposure. It is
scientifically accepted that there is a threshold for the
irritant response.
A chemical sensitization response is a far more complicated
physiologic effect. Some chemical sensitization responses are
mediated by the immunologic system, for others antibodies have
not yet been identified and the mechanism is as yet unknown. The
•ensitization response nay have one or more components, immediate
and/or delayed (8 hrs. after exposure). The response is similar
to an asthmatic reaction, it will not immediately resolve itself
upon cessation of exposure and may require medical treatment.
The key distinction between sensitization and irritation, is the
absence of a clear threshold in the former, once an individual
is sensitized, he/she will respond to low effect-triggering
•xposures. There is debate in -the scientific community as to
whether or not a threshold exists for the initial chemical
sensitizing event(s), but the data is not available to resolve
the issue.
5-7
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It is established that HCHO is a primary skin sensitizing
agent producing allergic contact dermatitis. It is also probably
a cause of immunologic contact urticaria (Consensus Workshop,
1984).
HCHO induces allergic contact dermatitis by a delayed type
(Type IV) hypersensitivity mechanism. Besides contact with HCHO
itself, allergic contact dermatitis can be caused by contact with
disinfectants and tissue preservatives containing HCHO, HCHO
releasers (resins in clothing, and paper products), and with
preservatives used for cosmetics, detergents, polishes, etc.
Table 5-2 illustrates some induction concentrations which
induce sensitivity and the range of challenge concentrations
which elicit the allergic reaction. The threshold for induction
has not been clearly defined, but it has been estimated as less
than 5 percent formalin in water * The appropriate threshold for
«licitation of allergic contact dermatitis in sensitized subjects!
ranges from 30 ppm for patch testing to 60 ppm for actual product
concentrations of HCHO (formalin). However, because of the
i
limited data base these estimates should be used with caution
(Consensus Workshop, 1984). Data (induction and challenge
concentrations) regarding the ability of HCHO-resin treated
textiles to cause contact dermatitis in garment workers for
instance are lacking.
5-8
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Table 5-2.
DELAYED TYPE HYPERSENSITIVIT* (HUMAN) DUE
TO LOW LEVELS OP FORMALDEHYDE*
Induction Challenge Results (No.
Concentration Concentration Reacting Humans)
370 ppm 3,700 ppm 0/45
3,700 pptn 3,700 ppm 4/48 (4.5%)
11,000 ppm 3,700 ppm 5/58 (5.7%)
18,500 ppm 3,700 ppm 4/52 (7.7%)
Unknown 30 ppro 4/8 (50%)
(clinical) 60 ppm 5/8 (63%)
100 ppm 6/8 (75%)
10,000 ppm 6/8 (100%)
Unknown 32 ppm 0/14
55 ppm 2/14 (14%)
144 ppm 7/14 150%)
•IRMC 1984a
The CIR Expert Panel (1984) stated that "the formulation and
manufacture of a cosmetic product should be s.uch as to ensure use
at the minimal effective concentration of formaldehyde, not to
exceed 0.2 percent measured as free formaldehyde."
HCHO skin irritation is non-immunologic; how its mechanism
may differ from other forms of dermal irritation is not known.
Induction of contact urticaria by HCHO has been reported and
is presumably a Type 1 allergy (Consensus Workshop, 1984).
However, proof that the immunological reactions are due to an
allergic response must await the demonstration of specific immune
reactions such as the production of IgE or igG antibody specific
for HCHO (IRMC Subgroup on Sensitization, 1984a). Nonimmunologic
contact urticaria which requires multiple applications at the
aame site has. been reported (Consensus Workshop, 1984).
5-9
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Sensitivity caused by the release of HCHO into the blood
from blood dialysis treatment has been reported. Frequent
eosinopnilia (increase in eosinophil leukocytes) and some severe
hypersensitivity and asthma-like reactions have been associated
with this occurrence. Antibodies reacting with HCHO conjugated
red blood cells is evidence of Type II auto allergy. The asthma-
like reactions are suggestion of Type I allergy (Consensus
Uorkshop, 1984). However, eonuaenting on this the IRMC Subgroup
stated th&t;
The hemodialysis patient population should not be
considered a source of IgE antibody since: (1)
formaldehyde levels present during dialysis have been
markedly reduced; (2) these reactions were due to
systemic exposure and primarily induced an antigenic
change in red blood cell surface markers; (3) only one
possible case has been reported of (anaphylactic)
sensitization by this route; this may resemble some
reactions caused by endotoxins present in dialysis
equipment. In this case patients were exposed to
allergens other than formaldehyde (personal
communication from Ronald M» Easterling, M.D.).
Consequently! results from hemodialysis patients should not
be generalized to indicate immunologic properties under other
(inhalant) conditions.
5.3. Cellular Changes
Inhalation exposure to HCHO causes a number of cellular
effects depending on the concentration and duration of exposure.
In the Kern et *!• (1983) study, rats exposed to 2.0 ppm
HCHO experienced rhinitis, epithelial dysplasia, and squamous
•etaplasia after 12 months of exposure. The frequency of
•quamous metaplasia increased to nearly 100 percent at the end of
the exposure period at 24 months. Considerable regression was
5-10
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noted at 27 months (see Figure 4-1). In a more recent study by
Tobe et al. (1985), slight increases in rhinitis and squamous
metaplasia were observed in rats exposed to 0.3 ppm for 28 months
and those found dead. However, the frequency of squamous
metaplasia falls within the 15 percent background rate for this
type of lesion as seen in the Kern et al. (1983) study.
A study by Rusch et al. (1983), which measured similar
•ndpoints in monkeys, rats, and hamsters, reported a NOEL for
squamous metaplasia of 1.0 ppm. Table 5-3 clearly shows that a
threshold for this response exists at about 1 ppm (rats in the
Kern study experienced squamous metaplasia at 2.0 ppm). A
similar threshold level is suggested for monkeys as Table 5-4
indicates. Although, the authors did not attribute the one case
of squamous metaplasia to HCHO exposure, it is possible that HCHO
is causing effects at or below 1.0 ppm due to the increased
incidence of nasal discharge in monkeys at 0.2 and 1.0 ppm as
illustrated in Table 5-5. Such a response may be due to damaged
cilia of the respiratory epithelium. Recently submitted data by
Woutersen et al. (1984b) on a subchronic (13-week) inhalation
toxicity study with HCHO in rats (10 rats per sex at each dose)
showed no squamous metaplasia in the controls, 3 of 20 at 1 ppm,
20 of 20 at 10 ppm, and 20 of 20 at 20 ppm.
5-11
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Table 5-3.
Significant Findings in Nasal Turbinates
in Rats*
Gr ou p
I (combined
(controls)
II
III
IV
Level (ppm)
Squamous
Meta/Hyperplasia
Basal Cell
Hyperplasia
0
0.20
1.00**
3.00
5/77
1/38
3/36
23/37
4/77
0/38
0/36
25/37
"Adapted from Rusch et al. (1983)
**NOEL
Group
I
II
III
IV
V
Table. 5-4.
Significant Findings in Nasal Turbinates
in Monkeys*
Level [ppm]
0
0.02
1.00«*
0
3.00
Squamous Meta/Hyperplasia
0/6
0/6
1/6
0/6
6/6
*Adapted from Rusch et al. (1983)
**NOEL
Group
(ppm)
Table 5-5.
Total Incidence By Groups of Monkeys*
II
Hoarse
Congestion
Nasal discharge
III
IV
(0)
0
0
9
(0.2)
0
0
30
(1.0)
0
0
45
(0)
0
0
5
(3.0)
32
36
62
•Adapted from Rusch et al. (1983)
5-12
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A recent report by Carson et al. (1985) in which ciliary
ultrastructure in humans (85 normal children) was studied before,
during, and after episodes of upper respiratory infection by
electron microscopy postulated that "the frequency and nonability
with which abnormal cilia appear may be related to the severity
and duration of clinical symptoms such as cough and rhinorrhea
(nasal discharge)." since ciliary structure is integrally
related to function, the low incidence of nasal discharge in
monkeys at 0.2 and 1.0 ppra may indicate ultrastructural damage by
HCHO to the mucociliary clearance system. Thus, monkeys (and
humans) may be more sensitive to the effects of HCHO than rats
(nasal discharge was not observed in rats).
The effect of HCHO on nasal mucociliary function in the rat
has been studied by Morgan et al. (1983b) (see Section
4.4.3.2.). Male Fischer 344 rats were exposed for 6 hours per
day for 1, 2, 4 or 9 days, to 0.5, 2, 6 or 15 ppm HCHO. There
was a clear dose-dependent affect on mucociliary activity. At 15
ppm there was significant inhibition of mucociliary activity
which progressed from anterior to posterior regions of nasal
tissue. Only slight effects were noted in animals exposed to 2
or 6 ppm. At 0.5 ppm no effects were observed. Whether
ultrastructural changes to cilia occurred below 2.0 ppm is
unknown because the endpoints being measured were mucostasis or
ciliastasis which was recorded by videocamera.
In summary, it is clear that observable cellular changes
begin to occur above 1 ppm HCHO, with the extent and severity
5-13
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dependent on concentration and duration of exposure. Based on
data developed in rats and monkeys the NOEL for squamous
metaplasia and rhinitis can be placed at 1.0 ppm.
Ultrastructural changes in the mucocillary clearance system may
be occurring as low as 0.2 ppm, although this is far from
certain.
The practical consequence of the cellular changes noted is a
disturbance of the snucoeiliary clearance saeehanism. since this
system is an important defense mechanism in the removal of
particulate matter, including microbes, impairment of this
defense mechanism may increase the susceptability of persons to
infections and other respiratory diseases (Proctor, 1982; Comroe,
Jr., 1974; Widdicombe, 1977).
5*4. Central Nervous System Effects
Reports in the literature link HCHO with a number of
behavioral and physiologic effects such as thirst, dizziness and
apathy, inability to concentrate, sleep disturbances, etc.
Central nervous system responses to HCHO have been tested in a
variety of ways, including by determination of optical chronaxy,
electroencephalographically, and by measuring the sensitivity of
the dark-adapted eye to light. Responses are reported to begin
in some persons at 0.05 ppm and are maximal in individuals at
about 1.5 ppm. HCHO at less than 0.05 ppm probably has little or
no objective adverse effect (NRC, 1981).
5-14
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5.4.1. Neurochemical Changes
Studies using radio labeled HCHO have shown radioactivity in
the brains of rats after inhalation exposures. However, the
chemical identity of the radioactive material has not been
determined.
HCHO has been shown to affect the firing rate of
nasopalatine and ethmoidal nerves of the trigeminal nasal sensory
system. Besides being able to effect changes in the respiratory
rate of animals, HCHO also appears to be able to depress
trigeminal nerve response to other irritants, although the data
in this regard are not conclusive.
Whether HCHO is capable of causing morphological changes in
the CNS is unclear. In two studies reviewed by the Consensus
Workshop (19B4), conflicting results were seen. In one study,
structural and cytochemical changes were seen in the cerebral
amygdaloid complex of rats exposed to 1 to 3 mg/in3 of HCHO for 3
months. In contrast, monkeys injected intravenously over several
hours with HCHO for a total dose of 0.9 g/kg showed no
histologically detectable effects in the CNS.
5.4.2. Human Studies
A number of reports are available which link chronic HCHO
exposure to a number of psychological/behavioral problems
including depression, irritability, nemory loss and decreased
attention capacity, and sleep disturbances. Unfortunately, these
studies for the most part have involved field surveys using
subjective self-report symptom inventories. Control data are
5-15
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often inadequate or completely absent. This is a significant
problem when dealing with HCHO, which in addition to any direct
toxic effects possibly associated with it, produces distinct
olfactory cues which may stimulate a spectrum of secondary
psychological reactions (e.g., expectancies, irritations,
anxieties, fears, etc.). These reactions nay in turn exacerbate,
•ask, or interfere with the more direct neurologic, biochemical,
and physiological responses to HCHO (Consensus Workshop, 1984).
Nine studies of human populations were reviewed by the
Consensus Workshop (1984), but most had serious methodologic
problems. For instance in studies by Dally et al., Sardinas et
al., Garry et al., and Woodbury and Zenz, health complaints such
as headaches and difficulty in sleeping were linked to HCHO
exposure. However, these studies do not include control
populations and suffered from selection bias.
Thun and Altman have pointed out some of the difficulties in
prevalence surveys of symptoms in residents from UFFI homes,
including olfactory cues, respondent and recall biases, and the
objective outcomes measured. No significant difference was found
in the occurrence of headaches or insomnia in residents of homes
with UPPI, compared to neighborhood controls.
In contrast, a study by Olson and Dossing found a
significantly greater prevalence of nose and throat irritation,
unnatural tiredness, and headaches in exposed subjects than in
controls. While this study overcomes many of the design problems
previously discussed, responses still may have been based by an
awareness of the subjects of the study goals and hypotheses.
5-16
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Attempts have been made to evaluate reported symptoms using
formal tests of neuropsychological function. A study by Schenker
et al. found that persons living in UFFI homes who had complained
of memory impairment had negative results on formal tests of
memory function, although positive findings were seen for many
regarding attention span. In addition, a study by Anderson found
no effect on performance tests of 16 healthy volunteers exposed
to HCHO under controlled laboratory conditions (Consensus
Workshop). A more recent study by Kilburn et al. of histology
technicians showed a higher prevalence of acute and neurological
effects such as headache, loss of balance, insomnia, memory loss,
etc., than in controls. When 25 technicians were evaluated using
neurobehavioral tests (block design, digit symbol, and embedded
figure), a few deficits were seen compared to expected results
/
(IRMC Subgroup on Systemic Effects, 1984b).
Commenting on the human data the Workshop Panel stated that
the information "suggests that formaldehyde may affect the
psychological functioning of the individual in three ways: (1)
directly, as a result of the immediate toxic properties of the
substance on the peripheral and central nervous systems; (2)
indirectly, as a result of the individual's monitoring and
awareness of the aforementioned changes and his/her
interpretation and reaction to such changes, which, in turn,
feeds back into the central nervous system; and (3) as a result
of the individual's psychological reaction and concomitant CNS
response to the olfactory properties of the substance, in
5-17
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practice, these processes are interdependent, yet this simple
analysis of a complex series of responses underlines the need to
control for 'expectancy' effects in formaldehyde research to
permit a differentiation of the direct effects of formaldehyde on
psychological functions from it ssecondary effects."
5*4.3. Conclusion
Based on the body of data available on the effects of HCHO
on the nervous system, the Workshop Panel concluded that:
The ®£f*ets of formaldehyde and/or its metabolites
on the biochemistry of the nervous system have not been
clearly defined. Various possibilities exist whereby
such effects might be mediated.
Some evidence exists that exposure to formic acid
(the principal metabolite of formaldehyde) in vapor
form at high concentrations exercises nervous system
toxicity in intact rats.
The irritant effects of formaldehyde may be
reflected in altered function of sensory nerves such as
the trigeminal nasal sensory system. The presence of
morphological changes in the CNS has been observed in
one study and not in another.
The difficulties inherent in any study of
psychological/behavioral effects of formaldehyde have
not yet been overcome in the course of conducting field
surveys.
Epidemiologic studies evaluating neuro-
psychological symptoms potentially due to occupational
or environmental exposure to formaldehyde have failed
to overcome the problems commonly associated with such
studies. However, some studies merit further
investigation.
5.5. OavclopBental and Reproductive Effects
5.5.1. Animal Studies
A number of studies have been reported which measured the
potential of teratogenic or reproductive effects of HCHO.
5-18
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Ulsamer et A!. (1984) reviewed four inhalation studies. No
teratogenic effects were reported. However, other effects in
dams and fetuses were reported.
A dermal study by Overman, as reviewed by Ulsamer et al.
(1984), reported that applications of formalin to the backs of
pregnant hamsters for 2 hours per day on days 7-11 of gestation
increased resorptions and birth defects. A repeat of the study
did not bear this out.
A study by Marks et al. was reviewed by the Consensus
Workshop (1984) which concluded that it was the only adequate
study of possible teratogenic effects of HCHO in mammals.
The Workshop review is as follows:
Harks and colleagues intubated pregnant mice on
days 6 through 15 of gestation with 0, 74, 148 or 185
ing/kg/day. At the highest dose, 22 of the 34 pregnant
mice died. At that dose, there was an increased
incidence of resorptions, but that increase was not
statistically significant. At no dose did the
incidence of resorptions differ between the treated and
control groups. There were also no treatment-related
differences in the mean number of implantations,
stunted fetuses, live fetuses per litter, or average
fetal body weight per litter. At a dose which killed
more than 50 percent of the dams, no adverse
reproductive outcomes were observed except for the
increase in the incidence of resorptions that was not
statistically significant.
To measure the teratogenic potential of HCHO generated in
vivo, a number of investigators exposed animals to hexamethylene-
tetramine by feeding or by drinking water. Studies by Delia
Porta et al., Hurni and Ohder, and Natvig et al. were variously
reviewed by the CIR Expert Panel (1984), Ulsamer et al. (1984),
MRC (1981), and the Consensus Workshop (1984). No malformations
were noted in any of the studies.
5-19
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The Consensus Workshop (1984) reviewed studies of
reproductive effects. in one study, prolonged diestrus, but no
impairment of reproductive function was reported. Ovarian
involution and endomentrial atrophy were observed in another
study, but only in female nice exposed to 40 ppm HCHO (a
concentration which killed 80 percent of the animals). Other
studies were reviewed but were found to be of little value
because of gaethodologie problems.
SǤa2<> Human Data
No data have been found linking HCHO to teratogenic effects
in humans. However, the Consensus Conference Panel stated that:
There is indirect evidence that would argue against
formaldehyde being a major human teratogen. Over the
last 30 years, the annual production and domestic use
of formaldehyde in the United States has gone up
fivefold from one billion pounds. Birth defects have
been reasonably stable over the last 30 years, although
in the last decade, there have been some exceptions to
this rule. The reported incidence of ventricular
fteptal defects and patent ductus arterious has
increased and that of anencephaly and spina bifida has
declined.
Review of reports of reproductive effects by the Consensus
Workshop (1984) and the IRMC Systemic Effects Subgroup (1984b)
did not lead to firm conclusions regarding HCHU's potential to
cause reproductive effects for a number of reasons. In a study
by Shumilina, workers exposed to urea-HCHO resins were reported
to have a threefold increase in nenstrual disorders and produced
•ore babies weighing between 2500 and 3000 g than the controls.
The IRMC Systemic Effects Subgroup concluded that because of a
lack of information on the worker environment and the
5-20
-------
socioeconomic conditions of the study and control groups, plus
the fact that other conditions such as stress and personal and
nutritional habits are associated with the effects reported, the
role of HCHO in the development of the reported disorders is
uncertain, in a better designed study, reviewed by the IRMC
Subgroup and the Workshop, Olson and Dossing studied a group of
female workers in a mobile hone day care center who were exposed
to 0.43 mg/m3 of HCHO, they reported increased incidence of eye
irritation, headache, and use of analgesics in the group. In
addition, 30 percent of the exposed group had a history of
menstrual irregularity. The Consensus Workshop (1984) felt that
these two studies point to the need for further research, but do
not show a cause-and-effeet relationship between exposure to HCHO
and menstrual disorders.
In two other reports reviewed by the IRMC (19845), an
increased incidence of miscarriages, changes in menstrual cycles,
and an increase in ovarian cysts were reported in one study of
female histotechnicians while a high incidence of sexual
dysfunction among male workers making fiber-reinforced plastic
was reported in another. In both instances, the workers were
exposed to chemicals other than HCHO, especially the male
workers, and the results may be due to the complex effects of
numerous chemicals, rather than HCHO alone.
The Consensus Workshop (1984) reviewed three studies related
to the potential of HCHO to cause germ-cell mutations. A study
by Fonlignie-Houbrechts reported increased pre- and post-
5-21
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implantation losses in the first week of mating, following
exposure of male mice to 50 mg/kg of HCHO by injection, and an
increase in preimplantation loss in the third week. NO evidence
of increased dominant lethal effects were seen in a study by
Epsteion et al. where nice were exposed at doses of up to 40
»gAg, IP. Finally, Cassidy reported increased sperm
abnormalities in rats exposed to a 200 mg/kg, but not in rats
given 100 rag/kg orally* "Thus the data are not consistent and do
not adequately test the possibility that formaldehyde causes
germ-cell mutations" (Consensus Workshop, 1984). However, these
data may not be inconsistent given different routes of
exposure. More work in this area may be needed.
Commenting on the possibility of one type of germ-cell
nutation the Workshop stated that "Human germ-cell mutations
causing nondisjunction could result in an increase in Down's
Syndrome. The constancy of maternal age-specific rates of Down's
Syndrome over the last 30 years, in face of increased exposure,
suggests that exposure to formaldehyde is not causing
nondisjunction in humans."
5.5.3. Conclusion
Ulsamer et al. (1984), the Workshop, and the IRNC Subgroup
concluded the following regarding the potential of HCHO to cause
teratogenic or reproductive effects*
Ulsamer et al.:
The currently available data do not show that the
embryo is unusually sensitive to formaldehyde nor is
there any information to show that formaldehyde is
teratogenic in rodents when administered orally or
5-22
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applied dermally in nontoxic amounts to the dams.
Also, the in vitro data do not provide any evidence to
support the conclusion that formaldehyde causes terata
at exposure concentrations that are not toxic to the
adult.
Inhalation of formaldehyde has caused fetotoxic
effects but not teratogenic effects. Further studies
of formaldehyde exposure by inhalation are needed to
elucidate the Meaning of these changes. Limited
evidence suggests that formaldehyde may affect the
Menstrual cycle and perhaps reproduction in women
repeatedly exposed. Additional work is needed to
validate these findings.
XRMC Subgroup:
Reproductive function depends upon a sensitive and
integrated feedback system between the nervous system
and the reproductive organs. Thus, many chemicals that
affect the nervous system have the potential to affect
reproduction. It is possible that formaldehyde, by
affecting the nervous system induces indirect changes
in reproductive behavior and reproduction. Although
•echanisms for such have not been delineated, several
recent reports that show an increase in the incidences
of brain tumors in humans exposed to formaldehyde
provide indirect evidence of the potential of
formaldehyde to significantly affect the CNS.
Consensus Panel:
In summary, the panel could find no evidence
clearly demonstrating that formaldehyde caused adverse
reproductive outcomes. What it found was a paucity of
information from which to make inferences and data that
suggested hypotheses to be tested in future studies.
This panel feels that formaldehyde poses little, if
any, risk as a potential human teratogen. This
judgment is based on the irritation potential of
formaldehyde at extremely low ambient concentrations
(0.05 ppro), existing data from in vivo mammalian
studies, and toxicokinetic and Metabolism data
indicating an extremely short half-life (not detected
to 1.5 Min) of the parent compound, and relatively
short half-life (80 to 90 nin) of the only known
Metabolite (formate) in the blood, regardless of the
route of exposure.
5-23
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5.6. Effects on Visceral Organs
The ,potential effects of HCHO on visceral oryans has
received relatively little attention. One recent review article
by Beall et al. (1964) summarizes the association between
exposure to HCHO and the liver. Based on the literature
reviewed, it appears that HCHO causes hyperemia or inflammation
in liver and kidney in rats. Microscopically, HCHO also causes
cloudy swelling, cytoplasraic vacuolization, and necrosis in the
liver, and hypereaia* edema, and necrosis in the kidney.
Macroscopic changes in the liver have also been produced by
HCHO. When exposure is repeated over a period of weeks, changes
include a mottled appearance and a decrease in liver weight.
Following a single high exposure, liver size may increase.
Effects on viscera could result from indirect mechanisms or be
secondary to other effects near the site of first contact. Under
some circumstances, GSH detoxification mechanisms may be involved
URMC, 1984b).
Transient effects on the hematopoietic system occurred in
rats and mice after 6 months of exposure to HCHO by inhalation.
These effects were reflected by statistically significant
decreases in (1) reticulocytes in female mice exposed to 2.1, 5.6
or 14,3 ppm; (2) mean corpuscular hemoglobin in male and female
rats exposed to 14.3 of HCHO} and (3) raean corpuscular hemoglobin
concentration in stale rats exposed to 2.1, 5.6 or 143. ppm of
HCHO. Male and female rats had significant (p<0.05) increases in
an corpuscular hemoglobin, mean corpuscular hemoglobin
5-24
-------
concentration, and myeloid to erythroid ratios after 13 weeks of
exposure £>y inhalation to 12.7 ppm of HCHO. This could indicate
myeloid hyperplasia or erythroid hypoplasia. Thus, it is
possible effects on visceral organs could be partially caused
through changes in the hentatopoietic system as well as through
other mechanisms (IRMC, 19845).
5-25
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6. EXPOSURE ASSESSMENT
6.1. Introduction
The sources of HCHO can be grouped into two major
categories: direct (or commercial) production and indirect
production. The chemical is not imported in any appreciable
quantities.
Commercially, HCHO is produced from the catalytic oxidation
of Methancl, using either silver oxide or a mixed-metal oxide as
the catalyst. Processes accounting for the indirect production
of HCHO include the photochemical oxidation of airborne
hydrocarbons released from incomplete combustion processes, the
direct production of HCHO during incomplete combustion of
hydrocarbons in fossil fuels and refuse, and certain natural
processes.
The 1983 commercial production of HCHO amounted to about 6
billion pounds. The major derivatives are urea-HCHO resins,
phenol-HCHO resins, acetal resins, and butanediol. The urea- and
phenol-HCHO resins account for about 53 percent of HCHO
production. Adhesives and plastics are the major end uses.
The "consumption" of HCHO can be broken down into three
najor categories: nonconsumptive uses, pseudo-consumptive uses,
and consumptive uses. In nonconsumptive uses, the chemical
*
identity of the HCHO does not change. In pseudo-consumptive
uses, the chemical identity of HCHO does change, but it is not
irreversibly altered. Under appropriate conditions, some or all
of the original HCHO nay be regenerated. Consumptive uses, on
6-1
-------
the other hand, are those uses in which HCHO serves as a
feedstock for the preparation of other chemicals. The
derivatives are irreversibly formed and usually contain only
residual levels of unreacted HCHO. Under extreme conditions,
•uch as very high temperatures or highly acidic conditions, some
of the derivatives may degrade and release HCHO.
HCHO's major nonconsumptive uses are (1) disinfectant, (2)
preservative, (3) deodorant„ and (4) textile and paper uses.
The major pseudo-consumptive uses are (1) urea-HCHO resins
which are used in fiberboard, particleboard, plywood, laminates,
urea-HCHO foams, molding compounds, and paper, textiles, and
protective coatings; (2) urea-HCHO concentrates which are used to
produce time-release fertilizers, and (3) hexamethylenetetramine
which is used as a special anhydrous form of HCHO to cure resins
and to treat textiles and rubber.
The major consumptive uses are (1) melamine-HCHO resins
which are used for molding compounds, fiberboard, particleboard,
plywood, laminates, paper and textiles, (2) phenol-HCHO resins
which are used in fiberboard, particleboard, plywood molding
compounds, and insulation; (3) pentaerythritol which is used to
produce alkyd resins, (4) 1,4-butanediol which is used to produce
tetrahydrofuran, (5) acetal resins which are used in the
aanufacture of engineering plastics, and (6) trimethylolpropane
which is used in the production of urethanes.
6-2
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6.2. Estimates of Current Human Exposure
To obtain estimates of human exposure to HCHO and its
products, the Agency commissioned a contractor study (Versar,
1982). This study integrated the existing monitoring data,
engineering or modeling estimates, use data, population
estimates, and assessment of the likelihood of exposure from
HCHO-related activities into an exposure assessment detailing
those activities having a high HCHO exposure potential. EPA has
updated some portions of this assessment to reflect new data
received in response to the FEDERAL REGISTER notice of November
18, 1983 and other data gathered by EPA. The combined data were
used as the basis for this risk assessment.
Since specific monitoring data for all types of potentially
exposed worker classifications or operational settings within an
industry were generally not available, all workers in a given
industry were assumed to be exposed to the mean exposure levels
reported for that industry; in this case garment workers. All
worker exposure, however, is not in fact identical; worker
exposure can vary because of the physical characteristics of the
work site and the employee's work station for example. However*
in the absence of data EPA must make reasonable assumptions
regarding exposure levels. Workers in the garment industry were
•
assumed to be exposed 5 days per week for 40 years. General
population exposures (conventional home residents) were assumed
to be for 70 years. Manufactured home residents were assumed to
be exposed 112 hours per week for 10 years.
6-3
-------
The reported exposure levels are assumed to be
representative of the actual exposure levels for a given
population. The limitation that this assumption presents is that
the estimated exposure levels for some populations may differ, in
•one cases widely, from the actual situation. This is especially
true for those populations or subpopulations for which little or
no monitoring data are available and also for those populations
for which the monitoring data were collected as a result of
complaint investigations.
€.3. Populations at Risk
As discussed previously the two populations at risk are
certain home residents and garment workers.
6.3*1. Home Residents
The current population of relatively new manufactured homes
is approximately 4,500,000. This figure includes those people
living in homes manufactured since 1976 (Versar, 1982). However,
prospective population estimates are also important. Based on a
projection of manufactured housing starts by Versar (1985a), it
is estimated that 6,642,000 persons will occupy a new
manufactured home during the next ten years. This figure assumes
295*203 starts per year and 2.25 persons per home. —
Similarly, 1,579,000 new conventional homes will be started
•
«ach year for the next ten years with an occupancy rate of 2.53
persons for a total of 40,011,000 persons.
6-4
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6.3.2. Garment Workers
The number of potentially exposed garment workers is
estimated to be 777,000 (Versar, 1982) out of 1,100,000 workers
employed in the U.S. apparel industry (Ward, 1984). This figure
•ay drop in the future due to increased foreign competition and
the introduction of labor saving equipment.
6.3.3. Summary
Table 6-1 presents population estimates for the two housing
segments and garment manufacture. Assuming that the number of
potentially exposed garment workers remains steady at 770,000,
then a total of 47,430,000 persons over the next ten years may
have the potential to be affected by HCHO's noncancer effects.
Table 6-1.
POPULATIONS AT RISK
Present* Future**
Category Population Estimates
per yr 10 yrs
Manufactured 4,500,000 664,200 6,642,000
homes
Conventional 100,000,000 4,001,100 40,011,000
homes
Garment workers 777,000 N/A N/A
* Versar, 1982
** Versar, 198Sa
6-5
-------
6.4. Sources of HCHO in Categories of Concern
The principal sources of HCHO in the two categories of
concern are HCHO-bosed resins, principally urea-HCHO (UF)
resins. In homes, these resins are used to bond the wood plys
used to make plywood and to bind the wood particle and fibers
used to make particleboard and medium density fiberboard. For
garments, HCHO-baeed resins are used to impart permanent press
finishes to the garments.
6.4.1. Homes
6.4.1.1. Pressed-wood products
Pressed-wood products are used in flooring, interior walls
and doors, cabinetry, and furniture. The three principal types
of products containing UF-resin are particleboard, medium-density
fiberboard (MDF), and hardwood plywood.
Particleboard is composition board comprised of 6 to 10
percent resin (by weight), and small wood particles. UF resin is
used in the majority of particleboard (about 90 percent). The
1983 production of particleboard was over 3 billion square feet,
of which 70 percent was used in furniture, fixtures,, cabinets,
and similar products. The remaining 30 percent is used for
construction, including manufactured home manufacture (common
uses are as decking or flooring underlayment).
MDF is also a composition board. It is comprised of wood
fibers and 7 to 9 percent UF-resin. Approximately 95 percent of
MDF production (over 600 million square feet in 1983) was used to
manufacture doors, fixtures, and cabinetry. The extent to which
6-6
-------
MDF is used in housing is uncertain and is probably highly
variable.
Unlike the two composition boards discussed above, hardwood
plywood is a laminated product; the resin is used as a glue to
hold thin layers of wood and veneers together. Of the nearly 2
billion square feet produced in 1983* 55 percent was used for
indoor paneling, 30 percent for furniture and cabinets, and 15
percent for doors and laminated flooring.
Each of the pressed-wood products described above contain UF
resins which release HCHO over time. The release is attributable
to incomplete crosslinking of HCHO resin during manufacture and
release of HCHO via resin decomposition or hydrolysis.
6.4.1.2. Other Sources of HCHO
Indoor HCHO concentrations may be attributable to sources
other than pressed-wood products containing UF resin. The other
sources can be characterized as follows:
o Urea-HCHO foam insulation (UFFI) (existing homes only)
o Products with phenol HCHO resins (PF)
— softwood plywood
hardboard
waferboard
oriented strand board
— fibrous glass insulation
fibrous glass ceiling tiles
o Consumer products that may contain HCHO resins
carpeting
upholstry fabric
drapery fabric
other textiles
o Combustion products
unvented kerosene and gas appliances
smoke from tobacco products
-- combustion of wood or coal in fireplaces
6-7
-------
o Outdoor air
ventilation system air exchange
Compared to pressed-wood products, with the exception of
UFFI, the other sources are usually minor contributors to HCHO
concentrations in conventional and manufactured homes.
6.4.2* Garment Manufacture
The principal source of HCHO in the garment manufacturing
workplace, is the release of HCHO from fabric treated with resins
that impart durable or permanent press properties. The textiles
normally treated are blends of cotton, acetate, and rayon. These
fabrics account for 60-80 percent of the textile produced
annually.
The resin of choice is dimethyldihydroxyethylene urea
(DMDHEU) and its alkylated derivatives. It is estimated that
approximately 90 percent of the durable press resin market is
accounted for by DMDHEU. Other resins used are urea-HCHO,
melajnine HCHO, and carbmate resins, plus a HCHO/sulfur dioxide
vapor phase process.
HCHO is released from treated fabric in three phases. In
Phase I, any HCHO loosely held by Van der Waal forces is released
as the fabric is dried. Release of HCHO by this mechanism is
usually complete by the time garment workers receive the
fabric. Surface desorption occurs during Phase II. This
represents the release of HCHO which is not covalently bound to
the fabric, and can last up to 240 hours. The material is
normally stored during this phase, and increased ventilation can
6-8
-------
increase the rate at which HCHO is desorbed. Phase III, in which
hemiacetal hydrolysis is the mechanism of release, is thought to
be the phase of HCHO release which results in worker exposure at
the manufacturing site. Release of HCHO by the hydrolysis
mechanism is independent of air changes, but dependent on
humidity and temperature (Ward, 1984)
ۥ5. HCHO Levels in Homes and Garment Manufacturing Sites
(.5.1; Manufactured Homes
BUD has recently promulgated changes in its Manufactured
Home Construction and Safety Standards (24 CFF 3280). That set
product emission standards for particleboard (0.3 ppm) and
plywood (0.2 ppm) as published in the FEDERAL REGISTER of August
9, 1984 (47 PR 31996). HUD believes that if the product
standards are met and no other major emitters of formaldehyde are
present (e.g., medium density fiberboard), ambient levels will
not exceed 0.4 ppm (0.15 ppm 10 year average) under certain
temperature, humidity, and ventilation rate conditions. The HUD
regulations, however, were designed to reduce acute reactions to
HCHO and are not based on HCHO's potential carcinogenicity in
humans.
EPA estimates an average ambient HCHO level of 0.19 ppm for
manufactured homes (Versar, 1985b). EPA has used this estimate
and the estimated 10-year average for homes built under the HUD
•tandard (0.15 ppm) in the quantitative cancer risk assessment.
Another study has reported average levels of 0.54 ppm for
manufactured homes less than three years old and 0.19 ppm for
6-9
-------
homes older than three years (state of Wisconsin, 1983). The
Exposure Panel of the Workshop (1984) reported studies that
showed average ambient levels of 0.38 ppm for manufactured homes
not subject to complaints about HCHO odor by residents, and
averages of 0.38 ppm to 0.90 ppm for complaint homes. Thus, an
unrealistic worst case exposure estimate was not used to estimate
human risk. Also, only 10 years of exposure were assumed for
aanufactured homes. Specific •xposure data follow.
Figure 6-1 details mean HCHO levels in manufactured homes by
year of manufacture. However, as Table 6-2 illustrates, reported
means for any given home age naturally mask variations in the
HCHO levels persons are exposed to. In relatively new homes,
levels above 1.0 ppm have been recorded. Consequently, due to
construction differences and differences in temperature and
humidity, new manufactured homes may experience episodic levels
exceeding 1.0 ppm. It is generally accepted that HCHO levels
decline with home age as Figure 6-2 illustrates. However, Figure
6-1 makes an additional point. The Conyers (1984) study,
initiated in 1980, showed mean HCHO levels for new mobile homes
of around 0.875 ppm. Studies begun in more recent years (Hodges,
1984; University of Texas, 1984; MHI, 1984) indicate that initial
HCHO levels in new homes have declined to below 0.4 ppm. This is
true not only of the MHI (1984) study that sought to test the
performance of a new home against the HUD standard, but also of
other studies in 1981 and 1983 of homes less than one year old
which showed levels around 0.2 ppm HCHO. This interpretation is,
however, based on a relatively small data set.
6-10
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: ji
.'i
I
8
tt-
w^
~ 5
9
•i-
• i-
9WIVII
• tt*« m mm* tnm mn mnvnn.
t=1
I I I
I l I 1
ntt nn
i i I l
raw INI itn
. . VtMtorMAMIFACfUllt
Figure 6-1. tevt is m MOBILE IIOMCS conNtvoMMMQ to vt AR or MANUTACTUMC
-------
Table 6-2 . kBMry of FonMldthyde Concentrations Husured in
OcHDlatnt AobUt Hants tft Kentucky fro* $*pt«**r 1979
through OMMfecr 1930
or
BlM)
Hin.
Hut eonc.
(Bern)
1979
1977
1976
1974
1973
1972
1971
1970
19*9
2-J
4-5
4-7
9-10
10-11
11-12
17
7
10
S
7
3
2
1
4
.n
44
.11
.12
.11
.10
.«
.01
.OB
O.U
0.01
0.10
0.06
0.04
0.04
0.04
0.01
o.w
0.01
O.04
1.43
1.99
0.«7
0.72
0.53
0.23
0.31
0.26
0.22
0.06
0.01
0.19
teuree: Ganyert C?*B4)
6-12
-------
FREQUENCY
<*
EXCEEOANCf
IfOtND
• fCNCtUT •> t.4
MEDIAN
0 *75 550 S75 1100 1375 1«SO 19» 7200 247S
3900 357S
NOME AGE. DAYS
-------
Levels measured at any one temperature and hu-idity can,
however, be misleading. Table 6-3 which illustrates the effect
of temperature and humidity changes on a 0.4 ppm reading at
25*C/50 percent relative humidity (the HUD standard) shows that
under more extreme conditions (30°C/70 percent RH), the predicted
l«vel would rise to 0.92 ppm. Changes in temperature and
Maaidity eould be ®atp®6t»d with diurnal and seasonal weather
"flageftafttions? 3&8n«s. witfeout. constant climate control would
therefore be affected.
These data illustrate clearly that HCHO levels in homes are
the functions of multiple variables; neither age nor temperature
and humidity, nor any other variables can account for all
variations in residential levels (Versar, 1985b).
As the foregoing illustrates, HCHO levels in new
manufactured homes were tending toward 0.4 ppm and in some cases
above, until about 1979. After that date, mean HCHO levels in
new manufactured homes began to fall or at best leveled off
slightly below 0.4 ppm. Even so, peak levels above 0.4 ppm can
be expected at times due to adverse temperature and humidity
conditions. The frequency for such peaks is not known with
confidence, but based on the data available (see Tables 6-4 and
.,4-5 5 and Pig iff e £-1) they could be expected to occur in a
, fc.j • «
substantial fraction of new manufactured homes.
6-14
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Table 6-3 . Potential Effects of leapt rature and dilative Muwidity
Changes on FonMldenyde Air Concentrations (pom)*
•elative hu»iditv
feaperature
trr (»•€)
•TF C20»C)
irr c»*c)
•VF (10*0
m
o.oe
0.15
0.24
0.40
401
0.11
0.19
O.K
O.S3
SOI
0.14
0.24
0.40
O.M
•01
0.1?
0.29
0.4B
0.79
101
0.19
0.33
O.M
0.92
Calculated veins •quationtln Myers, 198A which were developed
BriMrily frw tfau on relatively MH prttMd Mod products and new
IOKS. Asstffes « tfl^eratwre coefficient of 0.930 and a hunidity
coefficient of 0.0195. ASMBVS • base forMldenyd* •easunrant of
0.40 pp» at 2S*C and SO percent relative hunidity.
6-15
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Table 6-4.
FREQUENCY OP OBSERVATIONS POUND IN CONCENTRATION
INTERVALS BY CLAYTON ENVIRONMENTAL CONSULTANTS
Concentration
Interval (ppro)
0.0 -
• 11 -
.21 -
.31 -
.41 -
.51 -
.61 -
.71 -
08! -
.91 -
1.1 -
2.1 -
Number
.10 ''
.20
.30
.40
.50
.60
.70
.80
.90
1.00
2.00
3.00
of homes
Percent of Sampled Hones0
^0.5 yrs >0.5-1 yr All Homes
3.€
?9f
6.5
7.2
5.8
6.5
5.8
5.8
6.5
12.2
24.5
7.9
139
8.0
4.0
36.0
16.0
0.0
12.0
16.0
4.0
0.0
4.0
0.0
0.0
25
8.1
19.7
14.3
9.3
5.0
4.6
4.6
3.9
3.9
7.7
14.7
4.2
259
* 259 "noneprnplaint" mobile homes up to eight years old were
ssapled in 1980-1981.
-...«*
Source: Versar statistical analysis of data supplied by
Singh et al. (1982).
6-16
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Table 6-5.
FREQUENCY OF OBSERVATIONS POUND IN CONCENTRATION
INTERVALS BY WISCONSIN DIVISION OF HEALTH
Concentration
Interval (ppm)
0.0 -
.11 -
.21 -
.31 -
.41 -
.51 -
.61 -
.71 -
.81 -
.91 -
1.1 -
2.1 -
Number
.10
.20
.30
.40
.50
.60
.70
.80
.90
1.00
2.00
3.00
of observations
Percent of Observations8
£0.5 yrs >0.5-1 yr All Hones
2.63
29.0
0.0
10.5
10.5
13.2
10.5
7.9
2.6
2.6
10.5
0.0
38
3.8
13.6
21.1
14.6
11.3
12.2
8.9
5.6
3.3
0.0
5.2
0.5
213
14.1
20.4
18.4
14.0
9.2
8.0
5.2
3.6
2.2
0.7
3.8
0.3
976
a 137 •noncomplaint" mobile hones up to nine years old were
sampled in 1980-1981. Each home was sampled at least six
tines at nonthly intervals. The data in the table reflect
the results of 976 measurements.
Source: Versar statistical analysis of data supplied by
Wisconsin Division of Health (1984).
6-17
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6.5.2. Conventional Homes
The average HCHO levels reported in several monitoring
studies of conventional homes range from less than 0.03 to 0.09
ppm. Newer homes and energy efficient homes tend to have higher
formaldehyde levels (often exceeding 0.1 ppm) than older homes
. (Versar, 1985b). Much of this information was gathered in hones
fehut were used as controls in studies of UPPI homes. Based on
"/-fcfease data* SPA sstlsaatss an «v«r»g® BCHO level of around 0.030
to 0.050 ppm in conventional homes as a long-term average.
£*'•'
Specific exposure data follow.
The Lawrence Berkeley Laboratory (LBL) has summarized HCHO
concentrations in 40 residenital indoor environments since 1979
(Girman et al., 1983). They have found that HCHO concentrations
in homes designed to be energy-efficient are somewhat higher than
concentrations in conventional homes. The maximum reported value
is 0.214 ppm in an energy-efficient home in Mission Viejo,
California. Data are not sufficient to allow calculation of mean
levels.
As part of the development of an indoor air pollution model
based on outdoor pollution and air exchange rates, Moschandreas
et al. (1978) studied the patterns of indoor aldehyde levels
» These data can be useful if
tre assume HCHO constitutes 60 percent of total aldehydes, based
on LBL data (Girman et al., 1983).
* .*' *
The results in Moschandreas et al. (1978) concluded that the
17 houses had. an average aldehyde concentration of 0.09 ppm.
6-18
-------
Applying the 60 percent factor, the average HCHO concentration
for the houses would be 0.05 ppm. The highest mean for any one
home was 0.26 ppm; the range for that home was 0.2 to 0.45 ppm.
Another home with a mean of 0.20 ppm reported a range of 0.07 to
0.5 ppm. For no other conventional hone did levels exceed 0.4
ppm.
A University of Iowa Study (Schutte et al., 1981), performed
tor the Formaldehyde Institute, monitored 31 conventional*
detached homes not containing urea-BCHO foam insulation (UFFI)
for HCHO concentrations in the indoor air. Samples were
evaluated in relation to outdoor HCHO concentrations, age of the
home, and other environmental factors monitored at each of the
sampled homes.
The average indoor concentration found in the homes was
0.063 ppm (standard deviation * 0.064) with a range of 0.013 to
0.34 ppm. In only 5 of the 31 homes were average concentrations
higher than or equal to 0.1 ppm. The average outside HCHO
concentration was 0.002 ppm (standard deviation «= 0.0013). In
addition, the correlation (from a linear regression) of the
natural log [CH20] versus age of the home resulted in a
correlation significance at the 95 percent confidence level (R *
-0.42).
The 1981 Canadian study (UFFI/ICC, 1981) also studied non-
UFFI hones. Table 6-6 summarizes these data, showing that levels
in none of the 378 hones exceeded 0.2 ppm.
6-19
-------
Table 6-6. Comparison of Non-UTTI Canadian Hones
by Average HCHO Concentration
^ke^^^0fc^M^A
m^BJf^B^p*
<.o. «
.eu.«s 11 r
.on- .0*0 §7
.040- .055 *7
.05S-.070 10
.070- .085 15
.OB5-.10 —
.1-.15 9
.15-.20 1
toUU 178
"•—•••
12.7
19.4
15.7
17.7
7.9
4.0
—
2.4
0.3
100.1
Cwulative
percentage
12.7
«M
47.6
85.5
93.4
97.4
—
99.8
100.1
Source: IFU/ICC (1981).
6-20
-------
A report by Virgil J. Konopinski (1983) of the Indiana State
Board of Health summarizes the results of a series of
investigations conducted from 1979 through 1983 to determine HCHO
levels in conventional homes in Indiana. The purpose of the 1983
report was to compare the levels found in those homes using other
types of insulation. The mean HCHO level in the 120 homes
without UPFI was 0.09 ppm (0.05 for homes with UFFI). That mean
could be skewed by the maximum concentration of 1.35 ppm reported
in one home.
From April to mid-December 1982, Oak Ridge National
Laboratory (ORNL) with the U.S. Consumer Product Safety
Commission (CPSC) studied indoor air quality in 40 east Tenessee
homes. The objective of the study was to increase the data base
of HCHO monitoring in a variety of American homes and further
examine the effect of housing types, inhabitant lifestyles, and
environmental factors on indoor pollutant levels.
Homes to be sampled were selected based on a stratification
to ensure representative home age, insulation types, and heating
sources. All were voluntarily enrolled. Twice a month, four
samplers at each location monitored HCHO levels in three rooms
and outside the house. Samplers were exposed to the air for
24-hour periods. No modifications to the residents' life styles
were requested during these measurements.
Table 6-7 summarises these data by home age and season
(indicative of temperature and humidity). HCHO measurements in
the 40-home east Tennessee study led to the following major
conclusions:
6-21
-------
Table 6-7. CRNL/CPSC Man FenMlotbyd* Concentrations (ppm)
as a Function sf Aee and S*ascn (Outdoor fie^i Are
Uts Than 25 ppb Detection litiit)
Aft of fcoute Season
•11 •!!
0-5 years all
W15 years all
®13»r all
VMTB.. ^j.
fall
$-15 years Spring
euewr
fall
Older tpring
•Mr
fall
•IT fiprtaf
SHBKf
fall
-
0.0*2
0.004
0.042
«.«^
0.111
0.047
0.043
0.049
0.034
0.036
0.029
Q.026
O.OS2
o.§»
0.040
f»
0.077
0.091
0.042
®^42
0.102
0.055
0.040
0.048
0.03S
0.051
0.037
0.023
0.9ft
0.091
0.047
•
5903
S210
1211
4$%n
OfiV
1069
931
*26
S2i
159
757
141
364
K93
1?*
1574
n
40
18
11
11
Itott: x • wan concentrations.
* • sundard tftviation.
• • IMfctr Of •MCUTMBTttS.
BK trtth «nd wttlmt ITFl.
Source: MMftfeerne «l il . CW04)
6-22
-------
(1) The average HCHO levels exceeded 100 ppb (0.1 ppm) in 25
percent of the homes.
(2) HCHO levels were found to be positively related to
temperature in homes. Houses with UFF1 were frequently
found to exhibit a temperature-dependent relationship
with measured HCHO levels.
(3) HCHO levels generally decreased with increasing age of
the house. This is consistent with decreased emission
from materials due to aging.
(4) Elevated levels were found in new houses that did not
contain UFFI.
(5) HCHO levels were found to fluctuate significantly both
diurnally and seasonally.
Studies by Breysse (1984) evaluated conventional, non-UFFI
homes. The University of Washington studied 59 such homes;
private laboratories in the state studied an additional 25. The
frequency distribution for measured levels are presented in Table
6-8. A total of 6 of the 169 samples (3.1 percent) were over 0.5
ppm.
Traynor and Nitschke (1984) monitored indoor air pollutants
in 30 homes with and without suspected combustion (and other)
sources. The average HCHO level observed in all the test homes
was 40 ppb; a high value of 151 ppb was found in one of the
tested residences categorized as containing new furnishings and
new paneling as a suspected pollution source.
The results can be summarized as follows:
o The 4 homes with no identified source had a range of
means of 0.007 to 0.034 ppm.
o The 3 homes with new furnishings had a range of means of
0.015 to 0.061 ppm.
o The 4 homes with cigarette smokers had a range of means
of 0.032 to 0.060 ppm.
6-23
-------
Table 6-8. Frequency Distribution ef FonMldrtyde levels
in ttathingtor Gonvtntional Non-UTFI Hares
tration
!*»>
Sf U
Frequency
(perctnt)
>1.0
1DTAL CBCTVATIONS
2
I
41
•e
113
t
iS
H
I- 189
1.0
2.1
•^v • 5
TO.4
•6-24
-------
o The 18 homes with gas, coal, and wood fueled
appliances/heaters had a range of means of 0.012 to
0.056 ppm.
o The 12 homes with a combination of sources reported a
range of means from 0.013 to 0.064.
Variations in home levels could not be attributed to combustion
sources.
A downward tend in HCHO levels in conventional homes is seen
in Figure 6-3. The relative proportion of low HCHO levels in
hones has increased over the past six years, and the proportion
of high levels had decreased. The line of demarcation appears to
be between 0.05 and 0.1 ppm (the concentration range in which
earlier studies predominate over more recent analyses). Again,
these data are limited and caution in interpretation is
recommended (versar, 1985b).
6.5.3. Garment Worker Exposure
HCHO levels in apparel manufacturing facilities were
generally below 3 ppm prior to 1980 (see Table 6-9). OSHA had
established a 3 ppm TWA (time-weighed average) in 1967. However,
OSHA is presently considering establishing a new level. The
ACGIri (American Conference of Government Industrial Hygienists)
level is 1 ppm TWA. In recent years, however, HCHO levels
observed were generally below 1 ppm (see Table 6-10). The data
in Tables-6-9 and 6-10 must be viewed with caution because in
1983, NIOSH discovered that the commercially prepared inpregnated
charcoal tubes which had been used in previous personal
•onitoring studies were unstable. Thus, the monitoring data
above may be useless since the loss of HCHO from the tubes was
6-25
-------
100 -
5
U
Ml
I
K>
40-
20 -
MMtf.dfTtDATAI
HCNUntMil.1 tWOOAYA
7MAVMM AND NITKKE ItWTM DATA!
I I
0.01
01 - .05
>0.5 - 0.1 >0.1 - 0.2
CONCENTRATION Lf VU (Pfm)
>0.2-0.3
>0.3-0.4
-0*
figure 6-3. FREQUENCY DISTRIBUTION OF LEVELS IN CONVENTIONAL HOMES
-------
Table 6-9. PRE-1980 MONITORING DATA FOR GARMENT MANUFACTURING AND
CLOSELY RELATED INDUSTRIES
1|»t«tt
*)••; *«»-f»fMl«rl«HHi.nm««1
Wf/*^^*J^*rt
•.i
i •
s.«
tmt)
0.1 • t.l
. INC]
(i.t. • f til !••»». cUtft-
••f M«V*MM mrtl. tU.)
•s
is
•S
•S
IS
0.11 • 0.M (i*». mt/
f.t • I.I fit****. IH4)
«J
IS
n
I
IS
«c
f.100 •
1171)
I.IM
IITf)
O.OJO
e.t • j.> (Ct«n«|.«f«*. mo
e.»» • o.«t (mi)0
c.o«
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i
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IS
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i
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1.2
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9
IS
tm in.
«M<«tM » • CA*
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111.
l IIS «"»
ft ^—-
-•*t
tut
IS
6-27
-------
6-10. RECENT
^^^^^^fe
Rm
INDUSTRY
i
N»
00
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mt
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mi
fcritfH '•«*!••*
H. M
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target tot fklrt Mf. to..
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0.11 |fMl.
t.«
-------
I '
Table 6-10. (cotittlttttd)
I
N>
VO
sic
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MJf
1141
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to* OMfom U.
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O.IM.O jtlM.ar**. 1900)
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7JM.
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ten*.
-------
not consistent. Consequently, the HCHO levels recorded most
likely represent lower levels than actual conditions. The NIOSH
method at that time was also used by OSHA.
NIOSH subsequently developed a stable medium for collecting
the HCHO and did two indepth industrial hygiene studies. The
surveys «?ere done at two large manufacturing sites producing
men's dress shirts* ECHO exposure levels were determined for 54
of 72 job titles in two different plants. The number of
individuals within each job title whose exposure levels were
sampled was based on the total number of employees in that
category and reflect a 95 percent confidence level that the
highest and lowest exposed individuals were included in the
sampling. A summary of the data are presented in Tables 6-11 and
6-12. These tables show that all levels of exposure were less
than 0.51 ppm TWA. Also, as Table 6-11 illustrates, the combined
range of data was very narrow (0.01-0.39 ppm) for 5 of the 6
departments in the two plants. The range of mean concentrations
of all departments (0.13-0.20 ppm) is also very narrow and
compares well within the overall combined mean exposure level of
0.17 ppm, which was used for quantitative cancer risk
assessment^ In addition, the average exposure levels used in
£PA°s section 4(f) determination (EPA, 1984b), 0.23 ppm (area)
and 0.64 ppm (personal) (Versar, 1982), were also used for cancer
risk assessment.
6-30
-------
Table 6-11. NtOSII Nonltotltig
by Department
I
u»
trinwro>
CUTTIIW ^
(12)
(29)
COLLAR
(33)
(27)
PARTS
(30)
(K)
ASSEMBLY
(tt)
t>AcKA<5lH6
(•15)
(20)
ADMINISTRATION
(30)
(26)
1 o - 1
I ** 1
* n 1
« u - — |
1 fi 1
1 ° 1
Id 1
1 ° 1
1 tt 1
I ° 1
! a 1
I ° I
* M . , 1
* e |
i 0 1
' u I
€ ft •- 1
4 p _„— .,«.. |
C 0 1
* nO _.|
1 A 1
1 9 1
1 A 1
1 1 1
0 0.1 0*2 0.3 O.il 0.5 O.t
8 MOUR tVA FfcfcMALDEHYDe CoNc^NtRAtlON UVtL
-------
Table 6-12.
Ul
10
FORMALDEHYDEJOJfCEfttttATlON ItVEtS (PPM)
GARMENT MANUFACTURING
erm^tfttr
-SAMES RftBGE *mm*
AomittSTRAffON
CUTtlWe
COLLAR
PARTS
ASSEMBLY
PACKAGING
56
41
GO
76
159
65
0.01
<0.01
0.02
<0.01
<0.01
«0.01
- 0.51
- 0.39
- 0.39
- 0.55
- 0.35
- 0.27
0.13
O.iQ
0.1S
0.20
O.I/
0.1H
«o.oi - o.5i) co.l/)
-------
All of the determinations made in the NIOSH studies were at
one point in time and may not reflect the variation of exposure
over a longer period. Factors that could promote variation in
HCHO levels in these plants include variation in ambient
temperature, humidity, type of faerie or resin system, and volume
of stored materials or completed work.
The exposure range across departments, within plants, as
well as between plants, appears to be very tight. Both these
plants were large manufacturing sites, producing similar
products. Both plants had central ventilation/cooling systems.
This type of plant may potentially represent only 10 percent of
the total number of manufacturing sites (though up to 25-30
percent of the workforce may work in such plants) (Ward, 1984).
€.6. Summary
The data presented above indicate that HCHO levels in new
manufactured homes are generally below 0.5 ppn, with 10-year
averages for existing and new HUD Standard homes of 0.19 and 0.15
ppm, respectively. However, some fraction of new homes
experience peak levels that could exceed 1.0 ppm for periods of
time. It would be expected that as temperature/humidity exceed
75»F/50% RH, HCHO levels would rise as Table 6-3 illustrates.
Thus, depending on heating and cooling preferences, HCHO levels
in new hones may substantially exceed the reported mean for new
homes.
The situation is similar for new conventional homes,
although reported mean levels are lower, with long-term means of
6-33
-------
0.030 to 0.050 ppm. However, because conventional housing is
•uch more heterogeneous, peak levels in some new homes may
substantially exceed reported means. Although temperature and
humidity conditions play a large role, construction techniques
which tend to limit air exchanges, such as in energy efficient
hones, and building product mixes are also of major importance.
Reported HCHO levels during jjaoaent manufacture are below
!•& ppa &n& in sorae plants • toe low 9.5 ppm, and the NIOSH data
indicate rather tight ranges (none exceeding 0.51 ppm). However,
•uch of the reported monitoring data must be approached with
caution due to the technical fault discussed earlier. Building
design, ventilation, and temperature/humidity changes may be
responsible for daily or seasonal variations.
6-34
-------
7. ESTIMATES OF CANCER RISKS
The determination of individual risk can be made through the
use of epidemiologic or animal studies. Epidemioloyic studies
suitable for risk extrapolations are rarely available, however,
and are not available in the case of HCHO. Thus, human cancer
risk from HCHO must be estimated through use of animal studies.
This necessitates extrapolation front high to low doses because,
typically, test animals are exposed to concentrations much higher
than those expected to be experienced by humans. These
extrapolations are carried out by fitting mathematical models to
the observed animal data.
7.1. Risk Estimates Based on Squamous Cell Carcinoma Data
Data from two different studies were considered for their
appropriateness to this risk assessment, one by Kern et al.
(1983) (the CUT study), the other by Albert et al. (1982) (the
NYU study). A study recently received, the Tobe et al. (1985)
study, is being peer reviewed and will be compared with the other
HCHO studies. Dose-response modeling was applied to the CUT
data for Fischer 344 rats using squamous cell carcinomas of the
nasal turbinates as an endpoint. The NYU study provides
corroborating evidence of a similar response in another strain of
rats (Sprague-Dawley). That study, however, was not considered
appropriate for risk estimation since it contains only one .
exposure concentration, and, based on the CUT data, one would
expect the true dose-response curve in the experimental range
curve to be highly nonlinear. Although not statistically
7-1
-------
significant, ths squamous eeii carcinoma response in two B6C3F1
mice of the CUT study at 15 ppm is suggestive of carcinogenicity
from formaldehyde inhalation in another species due to the rarity
of this tumor. This data set was not considered for dose-
response modeling, however, because of the limited response at
the highest dose level. The CUT study was chosen as the source
of data for several reasons: it was an experiment by inhalation,
nfhich is the primary route of exposure to man? the quality of the
i-
study is considered to be high; and it includes four exposure
levels for determining the shape of the dose-response curve
(Grindstaff, 1985).
It was decided to estimate the risk of tumor to rats
chronically exposed up to time of death without intervention, or
to a terminal sacrifice at 24 months. With some adjustments for
earlier sacrifice kills discussed below? this was estimated from
the CUT data. The dosing regimen assumed is that of the CUT
study, where exposure was six hours per day for five days per
week. For estimation purposes, the animals that lived beyond 24
months included with the animals sacrificed at 24 months.
An adjustment was necessary to correct for animals that died
very early in the CUT study or that were sacrificed prior "to~~24
sionths. The rats that died prior to the appearance of the first
squamous cell carcinoma at 1! months were not considered at
risk. Rats sacrificed at 12 and 18 months would be treated as
though they would have responded in the same proportion as the
rats that remained alive at the rspective sacrifice times. From
7-2
-------
this approach an estimate of tne prooabality of death with tumor
within 24 months and an estimate of its variance was obtained.
The numDer of animals at risk, and the number with tumors that
would give the same estimates of mean and variance for a 24-month
study with no interim kills at 12 and 18 months was determined,
and used as the input data for risk analysis. The data adjusted
for sacrifice kills obtained in this manner are 0/156, 0/159,
2/153, 94/140 (figures rounded), at nominal dose levels of 0, 2,
6, and 14.3 ppm.
Another method, which was not used, would simply omit from
the analysis all rats sacrificed prior to 24 months. The data
adjusted for sacrifice kills by this method are 0/156, 0/159,
2/155, and 95/141. The two constructed data sets produce a
negligible difference in estimated risk at very low doses under
the dose-response model discussed below.
Ambient air concentration (ppm) is recommended as the dose
metameter at the present time in the absence of evidence
suggesting another dose metameter is preferable. It also
conforms with EPA past practice. An alternative method suggested
by Casanova-Schmitz et al. (1984) and Starr et al. (1984) using
data derived from the formation of HCHO-DNA adducts was not used
because EPA's interpretation of this data (as discussed
previously) leads to a different conclusion than the authors.
However, use of this data leads to a reduction of about a factor
of 3 at the UCL and 50 at the MLE.
7-3
-------
The multistage model without restrictions on the order of
the polynomial in dose was used to extrapolate risks. The
formulation of the model for quantal response data was preferred
to one including time as a variable. Based on simulation studies
conducted under contract to EPA, it was not at all clear that
inclusion of time as a variable would provide improved
estimation? and there would have been some question about the
validity of the results in this case, due to lack of knowledge of
the cause of death of experimental animals, and due to
adjustments made for sacrifice data (Howe et al., 1984). Risk is
summarized as model-derived point estimates and associated upper
95 percent confidence limits in the dose ranges of interest. The
latter corresponds to the number from a linearized multistage
model procedure.
All currently used mathematical models of dose-response
provide oversimplified descriptions of the carcinogenic
process. EPA generally recommends the multistage model because
of certain desirable properties: (.1) it is based on a generally
accepted concept that the carcinogenic process usually involves
multiple stages, one or more of which may be affected by exposure
to the agent being considered; (2) the model class is
-sufficiently broad as to include both nonlinear and linear
members, and is able to describe adequately most observed convex
dose response relationships.
Although arguments have been made that there may be a dose
below which the added risk of cancer is zero, there is no
7-4
-------
consensus within the scientific community on this topic. Through
use of mathematical models of dose-response, there is currently
no way to demonstrate either the existence or nonexistence of a
• f , *
threshold. In addition, if any thresholds exist, they are likely
to vary among members of the population at risk, and may be
modified by other environmental agents. Therefore, use of a
dose-response model incorporating a single threshold would
provide an estimate of an average population threshold that would
have little practical utility. In the absence of clear evidence
of a threshold and quantifiable supporting data that could be
utilized in risk assessment, it was felt that for dose-response
modeling of HCHO it should be assumed that there is no
threshold. Such a conclusion is supported by the Consensus
Conference on Formaldehyde (1984).
The likelihood of response should be treated as equal in
rats and humans for the same exposure regimen and proportion of
lifetime exposed. Although differences have been apparent in
susceptibility among the species that have been exposed to HCHO,
there are no data suggesting that man may be less susceptible
than rats.
The estimated risk to rats is based on the CUT dosing
regimen for a period of 24 months, which may need to be adjusted
upward to obtain an estimate of risk for lifetime exposure. It
may also be necessary to convert the estimated risk to a shorter
exposure duration in some cases, or to adjust for a different
exposure schedule (i.e., other than six hours per day, five days
7-5
-------
per week). However, there is little scientific knowledge that
addresses these problems. Consequently, each estimate of
lifetime risk from the model (assumed to be equivalent for humans
and rats as discussed in the proceeding issue) was multiplied by
the proportion of a human lifetime actually exposed.
Hypothetically, then, at an exposure concentration producing a
<&i£etiffie risk of 1/1000, the risk for exposure of half a lifetime
aras estimated as i/200Q9 Similarly* If exposure was for 45 hours
**~ " . .
per week instead of for 30 as in the CUT study, the risk
estimate would be multiplied by 45/30 = 0.5, giving 3/2000.
Exposure of half a lifetime but at 45 hours per week would give
.5 times 1.5 times 1/1000 = 1/1333. It should be noted that due
to the upward curvature of the dose-response curve the resultant
risk will be less than if the scaling factor were applied to dose
before substitution into the model if the factor is greater than
one, and would be greater if the factor is less than one (in both
instances the difference would be less than 2 fold). If the
response curve were linear there would be no difference between
scaling risk or scaling dose. It is acknowledged that this rule
for adjustment is based on very simplified assumptions.
The estimated individual and population risks to humans for
• • • - '••/' ~>f •**-.• '••••
the three categories of concern are presented in Table 7-1.
7-6
s,.
-------
Table 7-1.
ESTIMATED INDIVIDUAL AND POPULATION RISKS BASED
UPON SQUAMOUS CELL CARCINOMA DATA FROM CUT STUDY.
POPULATION RISKS (number of excess tumors) APPEAR
IN PARENTHESES BELOW INDIVIDUAL RISK ESTIMATES.
Category Population
Mobile Hone 6,642,000*
Residents
1. Based on
current
Monitoring
data
2. Based on HUD
standard
Manufacturers 777,000
of Apparel
1. OSHA standard
2. Personal
sample
3. Area
sample
4. NIOBH data
Conventional 40,011,000*
Hone Residents
Exposure
0.19 ppm
(112 hrs/wk
for 10 yrs)
0.15 ppm
(112 hrs/wk
for 10 yrs)
3.0 ppm
(36 hrs/wk
for 40 yrs)
0.64 ppm
(36 hrs/wk
for 40 yrs)
0.23 ppn
(36 hrs/wk
for 40 yrs)
0.17 ppn
(36 hrs/wk
for 40 yrs)
0.025 ppn
(112 hrs/wk
for 70 yrs)
Maximum Likehihood
Estimate of Risk
3 X 10~9 IB1]
1 X 10~9 IB1]
6 X 10~4
6 X 10"7 [Bl]
9 X 10-9
4 X 10~9 [Bl]
7 X ID'12 (Bl]
95 Upper
Confidence
Limit on Risk
3 X 10~4 [Bl]
(1993)
2 X 10"4 [Bl]
(1328)
6 X 10'3
1 X 10~3 [Bl]
(777)
4 X 10-4 [si]
(311)
3 X 10~4 [Bl]
(233)
3 X 10"4 [Bl]
(12,003)
* Population estimates are based on anticipated additions to the housing
stock between 1985 and 1995 as estimated by Versar (19855).
7-7
-------
7.2. Risk Estimates Based on Polypoid Adenoma Data
There appears to be little credible evidence that polypoid
adenomas progress to any of the malignant tumors seen in the Kern
et al. (1983) study. However, while the adenomas should not be
combined statistically with the sguamous carcinomas for hazard
identification purposes, they represent an endpoint that can be
quantified separately*
Because, it is beyond -the capability of the various
extrapolation models to fit data with a negative slope, an
alternative extrapolation procedure is to drop the two highest
doses and use the data from the 2.0 ppm rat exposure group
(straight line to zero). However, since the true slope of the
dose-response curve is unknown below 2.0 ppro, this approach may
vastly overestimate the true risk if the curve is convex, and
underestimate it if it is concave. The reason the occurrence of
polypoid adenomas has a negative slope probably lies with the
fact that the cell type in the respiratory epithelium from which
these tumors arise is lost sooner and to a greater extent with
increasing dose due to squamous metaplasia. The less respiratory
epithelium available the smaller the chance for adenomas to
develop.
Bisk estimates for polypoid adenomas appear in Table 7-2.
tor'polypoid adenoma as the endpoint instead of squamous cell
carcinoma there is no difference between the two procedures
described earlier to adjust for animals at risk. The first
observation of a polypoid adenoma was in a rat sacrificed at 10
7-8
-------
months. Eliminating all rats dead of any cause prior to that
time and applying the method used for the carcinoma data leads to
7/159 for the response at 2 ppm with 1/156 at control, the same
as if all rats dead prior to an including the 18 month sacrifice
were excluded.
Table 7-2.
RISK BASED OH POLYPOID ADENOMA DATA
Mobile Home
Residents
1. based on
current
monitoring data
2. Based on HUD
data
Manufacturers
of Apparel
1. Personal sample
2. Area sample
3. NIGBH data
*.••**«;•••*•' ""-
Conventional
DC
tidents
Dose
0.19 ppm
(112 hrs/wk
for 10 yrs)
0.15 pp^\
(112 hrs/wk
for 10 yrs)
0.64 ppm
(36 hrs/wk
for 40 yrs)
0.25 ppm
(36 hrs/wk
for 40 yrs)
0.17 ppm
(36 hrs/wk
for 40 yrs)
0.025 ppn
(112 hrs/wk
for 70 yrs)
Maximum Likelihood
Estimate of Risk
2 X 10'
1 X 10-3
8 X 10-3
r3
3 X 10'
2 X 10"3
2 X 10-3
95 Upper
Confidence
Limit on Risk
r3
4 X 10'
3 X 10-3
2 X 10-2
5 X 10-3
5 X 1(T3
4 X 10-3
-7_Q
-------
7.3. Uncertainty in Risk Estimates
Model-derived risk estimates should be viewed in the proper
context. First, the UCL should not be viewed as a point estimate
of risk. Generation of the UCL is a statistical method for
estimating the range in which the true risk may lie. The true
risk is not likely to be higher than the UCL, but it could be
lower.
As Table 7-1 illustrates, there is a wide range between the
MLE and UCL, approximately 4 or 5 orders of magnitude. This
illustrates the statistical uncertainty of the estimates
generated due to the input data from the study used, which in
this case is highly non-linear. For instance, the individual
risks for apparel workers range from 1 X 10~3 [Bl] to 6 X 10~7
(B1J. In addition, it has been shown that the MLE is sensitive
to small changes in response data when the response is very
nonlinear in the experimental range. For instance, the dose
giving a risk of 1 X 10~6 (MLE) varies significantly due to small
changes in the response data of the Kern et al. (1983) study
(Cohn, 1985b). The following illustrates this:
Response at 2 ppm Dose for Risk of
(malignant) 1 X 10~6 (MLE)
I. 0 (actual) 0.67 ppm
2. 1/1,000 0.0022 ppm
3. 1 0.0006 ppm
,•
Consequently, when modeling data that are very non-linear, one
should not place great certainty on MLE estimates.
7-10
-------
As discussed above, the major contributor to the uncertainty
seen in the risk estimates is the steep dose-response seen in the
Kern et al (1983) study. There were no carcinomas at 2 ppm, 2 at
5.6 ppm, and 103 at 14.5 ppm, which is a 50-fold increase for
only a 2.5 times increase in dose. If changes in respiratory
rate are taken into account (the rats at 14.3 ppm are receiving
the equivalent of a 12 ppm exposure—use of this data leads to no
significant change in estimated risks at exposures of concern)
(Grinstaff, 1985), there is a 50-fold increase for only a
doubling of the dose.
HCHO's ability to cause rapid cell proliferation, cell
killing and subsequent restorative cell proliferation, its
ability to interact with single-strand DNA (during replication),
interfere with DNA repair, its demonstrated mutayenicity, and the
fact that the dose was delivered to a finite area may help
explain the abrupt increase in the response. However, none of
these factors demonstrate the presence of a threshold or minimal
risk at exposures below those that cause significant
nonneoplastic responses such as cell proliferation, restorative
cell growth, etc. For instance, although HCHO causes varying
degrees of cell proliferation in the nasal mucosa of rats due to
HCHO exposure, it must be remembered that there is a natural rate
of cell turnover in this tissue. While it is low in comparison
to HCHO induced increases, it does provide the opportunity for
HCHO to react with single-strand DNA during cell replication
possibly resulting in a mutant cell which, if proper conditions
7-11
-------
are met, could result in a neoplasm. While an event such as this
may be rare, it is not unreasonable when one considers that the
opportunities for this event to occur are great due to the
immense number of cell-turnovers which may lead to defects in
some cells of the population of the individuals exposed.
It is often useful to compare the human risks estimated from
animal data to those risks observed in the epidemiologic
studies. For instancee if one takes the UCL for pathologists
exposed to 3.2 ppm HCHO and assumes that all the excess tumors at
the UCL would appear as brain tumors, then one would expect to
see a 130% increase in brain tumors in this population. However,
in the epidemiologic studies which showed significant elevations,
increases of approximately 200% are seen. This is true for
leukemias as well* The UCL would give a 70% increase whereas an
increase of 100% was seen,
The situation for nasal cancer is more complicated because
of the inability of the Hayes and Olsen studies to delineate
levels of exposure. However, if one chooses an exposure group,
such as furniture workers who may be exposed to both wood dust
and formaldehyde, one can make some observations. The reported
exposures for this group range from 0.1 to 1.3 ppm HCHO as a
;' - - I • ' - •*"''. '
8-hour, time-weight©d-averag@e This translates to an increase in
nasal cancer risk from 1.5 (50 percent increase) to 11.0 (1000
percent increase) at the UCL. In the Olsen et al. study, an
increase in nasal cancer risk of 60 percent is reported for HCHO
exposure when the analyses adjusted for wood dust exposure. The
7-12
-------
Hayes et al. study reports an 180 percent increase in nasal
cancer risk for HCHO exposed persons. Both these increases are
not statistically significant due to low power and the small
number of cases exposed to only HCHO. In fact, the Hayes et al.
study has only 4 percent power to detect the estimated (from the
UC1 and animal data) risk for an exposure of 0.1 ppm HCHO and 60
percent power for an exposure of 1.3 ppm HCHO. The reported
increases in nasal cancer risks in the Olsen et al. and Hayes et
al. studies are in the range of those risks which were estimated
from the UCL and animal data for furniture workers.
Thus, when individual tumor types are examined it can be
seen that the UCL is not indicating greater excesses than seen in
certain studies when uncertainties about exposure and the lack of
power to detect are considered. Although HCHO's potential
carcinogenic effects should not be limited to one site in humans
because they are not obliged to breathe through their noses as
rats are, the analysis described above does provide a crude check
of the risks derived from animal data and those seen in human
studies.
Finally, a factor that can have a major bearing on
population risk estimates is the quality of the available
exposure data. Assumptions made in reporting exposure levels can
have a major impact. For instance, it is not uncommon during a
•onitoring exercise to find a number of samples that are below
the detection limit of the analytical technique used. Thus, when
a mean exposure level is calculated it should be realized that if
7-13
-------
the nondetectable (ND) samples are counted as 0 the calculated
mean will understate the actual situation. Conversely, if the ND
samples are counted as the limit of detection, the mean will
overstate the true situation. Another factor that can skew
exposure estimates are changes in non-governmental exposure limit
recommendations and the number of years over which the data are
collected, since a number of years of exposure data are often .
used to calculate means, it is possible that the mean will be
-weighted by samples taken prior to changes in voluntary exposure
limits. Thus, the reported mean could be substantially
overestimating the true situation. For instance, in the garment
industry, HCHO levels have apparently been falling since the late
70's and early 80's as a result of increased concern and a .
downward revision of the ACGIH recommendation for HCHO.
Consequently„ an industry average calculated from data predating
1980 could cause the reported mean to be overstated. This may
have a significant impact on the estimated population risks. For
the apparel industry there are approximately 800,000 workers
exposed to HCHO. The mean personal exposure level used for the
section 4(f) determination and this assessment is 0.64 ppm which
leads to population risks of
-------
industry, and great confidence cannot be placed on an industry
mean as a fair representation of actual exposure levels in the
approximately 20,000 sites where workers are exposed.
The data for mobile homes is qualitatively better in its
ability to characterize this group because of a greater number of
well conducted monitoring surveys. Mobil home exposure studies
have been done by HUD, state and local government agencies, and
academic researchers. Although data is generally only available
to estimate 10 year averages, data from complaint and non-
complaint homes produce 10 year averages which range from 0.19 to
0.25 ppm.
7.4. Presentation of Risk Estimates
As discussed in "Data Selection for Quantitative Analysis"
above, the recommendation is that risk estimates should be
separately derived from sguamous cell carcinoma and polypoid
adenoma data. However, two positions can be taken concerning the
presentation of the risk estimates. One is to present risk
estimates separately for sguamous cell carinomas and polypoid
adenomas and explain the uncertainties associated with each. The
other is to add the risk estimates for an overall estimate of
carcinogenic risk. These are discussed below.
7.4.1. Separate Risk Estimates Derived From Squamous
Cell Carcinoma and Polypoid Adenoma Data
Because two risk estimates are presented, the significance
and uncertainties associated with each must be explained.
7-15
-------
The squamous carcinomas observed in the Kern et al. (1983)
study are frank evidence of carcinogenicity in the rat. The
response at 14.3 ppm HCHO was highly significant in both sexes.
While not significant at 5.6 ppm, the observation of two squamous
cell carcinomas in 240 rats is considered biologically
.significant, since the historical incidence of squamous cell
carcinomas in male and fsmale F-344 rats is 1 in 3,000 rats (NTP,
,1985). In addition, significant numbers of squamous carcinomas
were observed in rats in two other long-term inhalation studies
(Albert et al., 1982; and Tobe et al., 1985). Consequently,
there is little uncertainty about the carcinoma results.
There is a positive dose-response relationship for squamous
cell carcinomas in the Kern et al. (1983) study. However,
because of the nonlinearity of the dose-response relationship,
there is a wide divergence between the upper 95 percent
confidence limit (UCL) and the maximum likelihood estimate (MLE)
of risk. This introduces a large and variable level of
uncertainty into the risk estimates (see proceeding section—
Uncertainty in Risk Estimates).
The situation for the polypoid adenoma data is not clear.
First, the statistical significance is poor. The adenomas are
not significant at any dose level for male and female rats
separately. Only when the response is pooled at 2.0 ppm is there
.significance. However, even this is questionable since the
response rate in male and female rats is not comparable. At the
5.6 ppm level responses in males and females were significantly
7-16
-------
different from one another. Moreover, two of the responses at
2.0 ppm were borderline diagnostic calls between focal
hyperplasia and polypoid adenoma (Boorman, 1984), and if these
two responses are dropped, significance is lost at 2 ppm. Also/
there is a negative dose-response relationship. Although some of
this may be due to the replacement of nasal epithelium with
•quamous epithelium earlier and to a greater extent as dose
increases, this is not definite. Thus, it is difficult to
^characterize the relationship between HCHO exposure and the
polypoid adenoma response. Because of the negative dose-response
relationship, it was necessary to drop the two highest doses (5.6
and 14.3 ppm) and extrapolate from 2.0 ppm to 0 (a straight line
from 2.0 to 0 ppm). Thus, if the true dose-response relationship
is concave between 0 and 2.0 ppm, estimated risks will be too
low. If upward convex they will be too high (this seems more
plausible given the benign and malignant tumor responses in the
Tobe et al. (1985) study and the squamous cell carcinoma response
in the Kern et al. (1983) study).
As discusssed above, there is a greater level of certainty
in the squamous cell carcinoma response and risk estimates
derived from them. Conversely, because of the nature of the
polypoid adenoma response, its weak statistical significance at
best, and the manner of risk estimation, the confidence in this
response and associated risk estimates is .low.
7-17
-------
7.4.2. Calculate Risks Separately But Add The Risks
The rationale for this option is that the polypoid adenomas
together with the squamous cell carcinomas observed in the Kern
et al. (1983) study are an indication of HCHO's potential human
•carcinogenicity. Moverover, benign tumors may be expected to
appear in the human population (not just in the nasal cavity).
It aay also be assumed, that they have some ability to progress to
j^ "•-.•$#•
cancers as a result of the promoting activity of other agents.
Consequently, adding the risk estimates from the benign (polypoid
adenomas) and malignant (squamous cell carcinomas) data provides
an overall estimate of carcinogenic risk to humans.
While such a line of reasoning is plausible, a number of
factors must be considered.
First, if the separate risk estimates are added, that
estimated estimated from the squamous cell carcinoma data is
dwarfed by the estimated adenoma response. For instance, using
UCl's the risk to garment workers exposed to 0.64 ppm of HCHO is
1 X 10~3 using squamous cell carcinoma data. The risk based on
benign tumors at the same concentration is 2 X 10~2. Adding the
two estimates give a risk of 2.1 X 10~2. Following the
*6\iidelines (EPA,, 1984a) this would be rounded to one significant
.-.•figure* i*m*e 2 X 1&~2» Thus, the contribution to the risk
estimate from the frank experimental evidence of carcinogenicity
•„-
^3.8 removed. In addition, the uncertainties unique to estimates
of risk based on the squamous cell carcinoma and polypoid adenoma
data are not carried clearly forward in a combined estimate of
risk.
7-18
-------
The second, and major assumption is that there is
equivalence between benign and malignant tumors, i.e. a benign
tumor will progress to a cancer. This is necessary because the
combined risk estimate is nearly entirely weighted by a risk
component generated from the benign polypoid adenoma tumor
data. Since the estimate is presented as a cancer risk estimate,
, > ..,,£-
equivalence (progression) must be assumed. However, the basis
for this assumption must be reviewed. Certainly there is much
literature on the progression of benign tumors, but equivalence
is not automatically assumed, especially when the experimental
study (the Kern study) suggests otherwise (see p. 22—Polypoid
Adenomas/Other tumors Observed).
It may not be correct to assume that the majority of tumors
estimated for the human population will occur in the nasal cavity
since humans are not obliged to breathe through their nose.
Consequently, it may be worthwhile to look at the nature of
benign tumors seen in the nasal cavity of humans and animals as
well as in other epithelial tissues in humans.
As previously discussed, the nature and progression of
benign tumors in the nasal cavity of rats is poorly understood
(see Section 4.2.1.). The polypoid adenomas observed in the Kern
et al. (1983) study do not appear to be the benign counterparts
of the squaroous cell carcinomas or other cancers observed. The
•situation for humans is similar, although based on clinical
experience some generalizations can be made. However, it must be
remembered that the clinical cases are the result of diverse
7-19
-------
causes and may not share the same course as an HCHO-induced
lesion. The following discussion is presented to highlight the
uncertainty involved in any discussion of cancer induction.
Two common types of benign lesions seen in the nasal cavity
of humans are nasal polyps and inverted sinonasal papillomas
which are both polypoid lesions.
. nasal polyps are a eoesaon. clinical condition in humans and
•»-*"
*sir@ -frsgwently associates with allergic rhinitis, inflammatory
diseases, and other disorders (Paludetti, 1983; Jacobs, 1983;
Prazer, 198-4r Drake-Lee, 1984). These polyps are not considered
to be true neoplasms, but are merely inflammatory hypertrophic
swellings (Robbins, 1974).
On the other hand, inverted squamous papillomas are true
neoplasms* Inverted squamous papillomas have an incidence that
is reported to vary from 0.4 to 4*7 percent of all nasal and
sinus neoplasms (Bosley, 1984; Hyams, 1971; Sellars, 1982;
Lampertico et al., 1963; Seydell, 1933). Their morphology may
vary from that of firm, bulky, opaque polypoid lesions with
marked vascularity to having the same appearance as common
inflammatory nasal polyps (Bosley, 1984; Perzin et al., 1981).
The reported associated frequency of squamous cell carcinoma with
. iiwartad papillssaa is between 2 -to 50 percent (Bosley, 1984; :
Hyams, 1971; Snyder et al. 1972; Ridolfi et al., 1977; Lasser et
al., 1976; Vrabec, 1975; Osborn, 1970; Yamaguchi et al.,
Brown, 1964).
7-20
-------
Two other types of benign neoplasms are seen in the nasal
cavity of humans; fungi form papilloraas and cylindrical cell
papillomas. Fungi form papilloraas are not associated with the
development of malignancy while the cylindrical cell papillomas
are associated with malignancy in 10 percent of the cases studied
(Bosley, 1984).
A number of benign tumors are seen in the oral mucous
membrane of humans. Fibroaas, papillomas, hemangioraas,
lyrophangiomas, and less commonly myoblastoraas and congenital
epulis. However, in contrast approximately 90 percent of oral
•
. •
malignancies are squamous cell carcinomas (Robbins, 1974).
The two most common benign tumors of the human larynx are
polyps and papillomas, other less common types run the gamut of
every cell type found within the larynx (Robbins, 1974).
Squamous papillomas are the most common type of benign tumors
seen in the larynx and are the most common of all childhood
laryngeal tumors. These are frequently divided into adult and
juvenile groups. However, recent work has contradicted some of
the classical descriptions used to separate adult from juvenile
papillomas (Nikolaidis, 1985).
However, while juvenile papillomas are thought not to, or to
rarely, undergo malignant transformation (Nikolaidsis, 1985; and
Robbins, 1974) the adult type is regarded as having the potenital
to progress to a malignancy (squamous cell carcinoma) (Robbins,
1974). In a study of 83 cases (73 juvenile and 10 adult) of
tumors of the' larynx, only one adult case was associated with a
7-21
-------
squaraous cell carcinoma (Nikolaidis, 1985). This suggests a less
than one-to-one relationship between papillomas and carcinomas:
it should be pointed out that there was surgical intervention and
no follow-up.
Although the above does not show that benign tumors caused
by HCHO will not progress to a malignant neoplasm, it does show
uncertainty involved in assuming that there is a one-to-one
^,
between risk estimates generated from benign and
malignant data sets.
7.4.3. Summary
Because of the uncertainties associated with the polypoid
adenoma data set, its statistical significance, the manner of
risk estimation, and the question of progression to malignant
tumors, it is recommended that risk estimates derived from them
not be added to estimates derived from squamous cell
carcinomas. In addition, it is recommended that greater weight
be given to risk estimates derived from squarnous cell carcinomas
because of the frank expression of carcinogenicity in the rat,
they are statistically significant, and there is a positive dose
response relationship.
7-22
-------
8. ESTIMATES OF NONCANCER RISKS
0.1. Introduction
Although some of HCHO's noncarcinogenic effects are well
characterized, there remains the problem of determining the dose-
response characteristics of populations for these effects. To
determine if dose-response relationships can be drawn from the
human data, six cross-sectional and two controlled human studies
were selected for review.
8.2. Studies Reviewed
Taole 8-1 presents the exposure-response relationships, if
any were observed, for those studies identified by Fraenkel, et
al. (1985a). From this group of studies, selected ones were
extensively analyzed for dose-response relationships. These
studies are detailed in Tables 8-2 and 8-3. In addition, several
studies which were thought to illicit a possible dose-
relationship, but were not identified in Table 8-1 were
extensively analyzed. The studies are ones which contain
information on both HCHO levels and characterization of
response. Studies which examined dermal responses were not
selected since exposure is by either patch testing or dermal
injection. Results from this route of exposure are often
difficult to generalize. The studies selected for Table 8-1
in-depth review were of two types; cross-sectional and controlled
(clinical). The cross-sectional studies were of mobile home
residents and occupationally exposed workers. In the clinical
trials, small groups, fewer than 20, of healthy volunteers were
8-1
-------
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•ftf ~f«re««
rtc —
'« ~ftM M «M
•M —
-------
Table
SMtalletf
CMtrcIt
•Mlytlt
B.t
•Ilk
N.4 V 4.1 »<0
. ». t. Mi
C. «. NUcftttt (I9IS|
0*«rte •«** •Ntraettati tCMMllcMt
ttltaM te.»p«»
•»»-««
oo
i
•twttt MS »«
-------
8-1.
Statlvlfcal
NwrH, t. I. tmj| totVttlHt
SriMrtt. t. tt «t. Ata
IIW3)
V ff ^A Aft
M* C* ^n QV*
f^^l • •
n^vv^ w» w«
C.0.
00
c r *
HHft tat
•T fartaWMiy* «• MC«I
frKtlw not k
*M *•
I»M
••» c««N» ftoft
1 !«•!«:
M
Itt
»
U
fcrttotl*
M If
V Br
1 CMt* r*tk tt«rl«4 Mltlilil
M
17.9
B.IK ««•
t«m
14/19
If/19
i/n • f
IN * iffiMM wrfwrt Ml |Mftf» rmttan t* fMdi tat
n t
» t
M t
• ^
I^
IkH
toll to •» c«tr«t«{ «• «Mlflllf*t 4M«
-------
teble 8-1. !•"*•••«
IMC
SUtHtktl
wftft tfpff
tMI
h «t
CO
I
00
-------
•ttble 8-2.
OP SELECTED CRHPS SMCT10NAL J
.*.
EXPOSURE
LFVFL (ppm)
SYWTOHS
SUBJECT OP
ESTIMATED
PREVALENCE
STUDY
Q'fMLNl'S
CoW
Any nasal
aluuLmallty
Senorrnea
FicsouL'c in
mucous mciil itanos
0.037
00
I
6 phleqm
Itch
Paah
shortness of
breath
Chest sputnun
nurnlnq sensation
in heart region
finales OW.yrs)
femalos (S-15 yrs)
fewalos O16 vr«?)
males * fowales
Oil yrs)
males ft females
males (>16 vrs)
females (Sr-lS vrn)
males ft females
Oil yrs)
50 non-
hejtamrthvlene-
tetrawine workers
ream cinol
% «4<«l»t?
Prevalence ratio calculate rom
and prevalence are represented.
i« 9» w?^i«al. interview. ....... ,
in the clinical examination nf individuals.
data
-------
Tfetole 8-2. (Continued)
(ppm)
0.19-0.44
SUTVJFTT
o.«2-o.ns
,
feraistent ceoqh
6 phlegm
Itch
Rash
Shortness of breatt
^^Hj^^^^KAV ^••nno^W uAn4BM.
tneSu BpsutawW
Burning sensation
S2 bexanetbylene"
tehranine
roRorcinol workers
i
13%
3*>*
23*
19*
23*
17*
in hentt
irritation
irritation
eye Irritation
flimmitis
Nbee, thirant
Irritation
34 oemanent
care center staff
7H mobile home flay
care center shaff
23*
57*
!*•*
73*
Control 'iixxip anr' 34
mobile hone day carr> centers.
-------
Tattle 8-2.
LFVEL (ppm)
<0.10-2.R4
SWMIMS SUWFCT OF fTTTTY
Burning eyes "esitlents of
Vfctering eyes mnoile IR)HVJS
nty throat
PRFVATOICT STtlHY OJfTNir.
25* Anderson Study of mohilo homes.
2ft* et al.
24*
0.1-3.0
09
I
Swollen giants
niarthea
Running nose
Freezing
Phlegm
Wheezing
Cough
Headache
Rash
y thmat
Counh i
Resfn.nali.Jiy
niarthea
Mausea 6 vomiting
£*in rash
Mults
0-12 yr?
Mults
V12 yrs
0-2 vrs
0-12
Milts
3-17 vrs
0-2 yrs
Mults
3-12 vm
0-2 vrs
Mults
3-12 vrs
0-2 yrs
MuJts
3-17 yrs
0-2 yrs
in*
2^*
17*
44*
29*
11*
79*
60*
3P*
54*
61*
36*
24*
27*
in*
SO*
3R*
0*
20*
lr>*
.3R*
0*
Carty et al
Mobile homes.
Measurement of Formalrfrhyle
vary with month of measurement.
50*
-------
Tab!® 8-2. (Continued)
LJVFI,
T OF
PRWALFNCE
OJMWIIIKJ
Coucjh
Phlegm
CO
I
M
K>
rynpnea
Prefient-linc
>*» yrs
1-* yrs
<1 vr
Previous on line
Never on linr
Present-line
>5 VTB
1-5 yrs
<1 yr
Previous on line
Never on line
Present line:
>•> vrs
1-S yrs
<1 yr
Previous on line
Mevcr on line
30%
12.5%
6.7*
26.7t
O.P*
6.7%
6.7*
20.0%
20.7*
12.S*
r, Mitchell
W filter iwnufacturinr! %.0?>) amonq any of tile qroui
in either FVC or PBVi ... ftie
X • •" i
(jroupr present line inoine than
5 yean or more, hart a lower
FPV« o/PVC ratio; and siiqnifi-
oantly lower CixO.05)
than the never-on-lino
-------
Table 8-3. SUMMARY OF SFLFCTED COITTRDLLED HITMAN STVDIFS
Levels of
Exposure (ppm)
Symptom
Study Subject
Response
Author
0
0.1
0.2
0.5
1.0
.
Odor perception
Conjunctival
sensitivity
Nose, Throat
sensitivity
Throat dryness
Oflor perception
Oonjunctival
sensitivity
Nose, "hroat
sensitivity
Throat dryness
unor perception
Conjunctival
sensitivity
Nose, Throat
sensitivity
Throat drynesfi
Odor perception
Oonjunctival
sensitivity
Nose, Throat
sensitivity
Throat dryness
Odor perception
Oonjunctival
sensitivity
None, Throat
sensitivity
Throat dryness
Anatony lab students 138 Raderb
Bach group contains 25
six students
20
0
14
15
21
15
35
35
35
2
30
IB
20
4
40
30
40
2
represents the log of a weiohted averaqe of the concentration x tine-factor.
response trend was observed for all conplaints.
8-13
-------
Ifeble 8-3. (Continued)
Level of
ure (ppn) Synptom
Study Subject Response
Author
3.0
S.O
Odor perception
Gonjunctlval
sensitivity
War perception
Conjunctival
aensitivity
Nose, Throat
sensitivity
Throat dryness
30
80
75
20
190
200
in
0.24
0.40
0.80
1.60
Conjunctival
irritation and
dryness in nose,
throat
Conjunctiva!
irritation and
rtryness in nose,
throat
Conjunctival
irritation anfl
dryness in nose,
throat
Conjunctival
irritation and
dryneas in
threat
Healthy students
2C (19%)
S (31%)
15 (94%)
Anderson
and Molhave
c tJurrter of oonplaints anong 16 subjects after a 5-hour exposure to forral«*ehy»te,
8-14
-------
exposed to varying concentrations of HCHO and their responses
were recorded. Set endpoints were examined such as, odor
recognition, conjunctival sensitivity, nose/throat sensitivity,
and throat dryness. The cross-sectional studies recorded a wide
range of health complaints as Table 6-2 illustrates.
S.3. Limitations of Studies
Even though dose-responses are identified, the studies
reviewed have major limitations which prevent their use to infer
the magnitude of general population risks.
8.3.1. Study Design Limitations
The data on acute effects come from controlled human studies
or cross-sectional studies. The majority of the studies were
designed as cross-sectional studies, also known as survey
studies, where both a random or nonrandotn sampling frame was
employed.* In addition, two of these studies' designs did not
incorporate a nonexposed or control group (Garry et al. and
Anderson et al.). Without a control group, it is impossible to
determine the magnitude of a reported symptom.
A cross-sectional study measures the study factor level, in
this instance the HCHO level, and disease outcome at the same
time. This type of study does not incorporate a follow-up period
•o that the prevalence of the disease outcome, and not the
*0se of a nonrandom sampling frame prevents extrapolating the
results beyond the studied population. Random sampling, on the
other hand, -allows the making of statistical inferences from
the studied population to the general population.
8-15
-------
incidence, is obtained.* Cross-sectional studies are often used
to generate hypotheses, but they have serious limitations in
making causal inferences.
Controlled human studies test etiologic hypotheses and can
identify acute effects. The two controlled human studies
identified in Table 8-3 did not utilize a randomization scheme.
Study participants were self-selected and may not be
representative of the general population.
8.3.2. Bias Limitations
Other limitations regard potential bias in the results. The
cross-sectional studies do not control for confounding exposures,
such as smoking or other occupational exposures and an observed
effect may not solely be due to HCHO exposure. Second, many
studies report subjective or self-reported symptoms. These
symptoms have not been medically verified, and thus results based
on subjective measures may be biased by over-reporting or under-
reporting. A third problem of the cross-sectional studies
concerns the quality of the environmental exposure measurement.
HCHO levels vary depending on the season of the year, hour of the
day, temperature, and humidity* These factors must be known when
evaluating the intensity of the disease »ndpoint.
S.4* Sssults
The principal acute effects of HCHO, reported by all studies
which were extensively examined (Tables 8-2 and 8-3), are that of
•Prevalence is the number of cases existing with the outcome
•t a single point in time. Incidence is the number of new
cases observed over a period of time.
8-16
-------
irritation to eyes, nose, throat, upper respiratory tract and
skin.
Evaluation of the results documented in the different papers
indicates that these effects exist in varing degrees in people
exposed to HCHO. These levels may range between 0.037-3.0 ppro.
However, the intensity of these symptoms differ depending on the
location of the study (mobile homes, industry, anatomy lab), on
ambient air conditions, and on individual characteristics and
personal habits.
Pour of the studies (e.g., Texas Indoor Air, Anderson et
al., Garry et al., and Olson and Dossing) were of occupants in
mobile homes. Among the mobile home studies, the symptoms with
the highest prevalence across different age groups were
headaches, muscle aches, eye symptoms (burning eyes, watery eyes,
itchy eyes), nose symptoms, and coughing. Some differences were
detected among the different age groups. The youngest groups (0-
2 yrs) experienced a higher rate of diarrhea while the adults had
a relatively high rate of complaints from headaches. Only the
Texas Air Quality study reports significant increases in the
prevalence of certain acute effects such as headaches, sneezing,
and nasal symptoms among occupants exposed to either 1.0 ppm HCHO
or greater, or 2.0 ppm HCHO or greater.
When evaluating these studies, it must be noted that not
only ambient conditions within the home, but also seasonal
temperature/humidity fluctuations can affect the rates of off
gasing (Gamble et al.). Because most mobile homes are tightly
8-17
-------
sealed and do not use a continuous influx of outside air, other
gases such as carbon monoxide, which were not measured, nay
contribute to the acute effects experienced by the residents.
Kerfoot and Mooney also reported nose and eye irritation in
morticians. These results are qualitative in nature; they
indicate that morticians who spent more time embalming than in
general funeral work Bore @ft«n eonplai'n'ted of upper respiratory
In studies of workers in industry, statistically significant
increases complaints from acute sensory effects were observed
among workers exposed to HCHO. The reported symptoms, itch,
rash, breathing better away from work, cough, chest tightness,
burning eyes, running nose and burning sensation in the heart
region were significantly increased in a group exposed to HCHO
when compared to non-HCHO workers. In addition, two studies
measured lung function in HCHO resin workers and in filter
manufacturing workers. Both studies observed significant
decreases in various lung function parameters, but neither study
reported the same observation. Exposure levels ranged between
0.02-0.66 ppm. When these two studies controlled for smoking
and/or drinking, the observed decreases in lung function
@sasu?@ra@nts remained. The studies do not identify other
occupational exposures <> It is not known whether the observed
effects were due to possible interactions.
Rader tested student volunteers in an anatomy laboratory and
found that the concentration levels of HCHO in ambient air are
8-18
-------
affected by seasonal changes, time of measurements, room
temperature and humidity level. Dose and response showed
correlations and there was a statistically significant increase
in each of the dosed groups and the control group for the total
complaint score* of acute effects* The summed complaint score
was for the acute effects: odor perception, conjunctival
sensitivity, nose/throat irritation, throat dryness, nasal
secretions and tear flow.
Andersen and Molhave assessed the human health effects
associated with prolonged exposure to HCHO under controlled
thermal and atmospheric conditions. They observed an increasing
trend with eye and nose irritation between exposure levels of 0.3
to 2.0 mg/m . Human response increased from 19 percent to 94
percent over this exposure range. In addition, mean mucous flow
rate decreased at the higher concentrations of HCHO. Changes in
airway resistance were significant for nasal pressure drop, vital
capacity, a several lung function parameters.
The above studies report eye, nose, throat irritation, and
upper respiratory effects with low levels of HCHO exposure, but
this information should be judged with caution since in most
cases:
o Effects are judged subjectively as symptoms experienced
by the subject and not as objective measurements.
o Limitations of the studies include small study sample
sice, selective study populations low response rates,
inadequate control of confounding variables, and
•It must be noted that the complaint score was a sum of the
number of complaints times the severity of the response.
8-19
-------
inability to distinguish the contributions of HCHO from
those of other substances.
8.5. Discussion
Both HUD and OSHA have assessed the acute effects due to
HCHO. HUD*s assessment was used to support changes in the
Manufactured Home Construction and Safety Standards, while OSHA's
assessment will fee «8©cJ to support » possible change in OSHA's
HDD's assessment consisted of an evaluation of the cost-
benefit relationships of regulatory alternatives to control HCHO
levels in mobile homes. A computer model was developed to assess
the relationship between HCHO levels and mobile home age. The
cost of illness was calculated for a 20-year exposure period
under various assumptions, such as initial HCHO concentrations in
homes, type and cost of resulting health effect, and number of
heroes and persons affected. HUD used the CPSC injury-cost model
to estimate an average cost of illness assuming that exposure to
HCHO could cause one of several types of health problems (i.e.,
ingestion of a foreign object, aspiration of a foreign object,
dermatitis of the face, or dermatitis of the eyeball). The HUD
study did not report the incidence or prevalence of symptoms for
persons s:®siding in homes with varying detectable levels of
^HCHO» .HUD's study saethod assumed that 75 percent of the
occupants of a mobile home with HCHO would experience a health
problem, but the concentration producing this effect was not
derived or estimated.
8-20
-------
There were no data presented in the HUD analysis which
supports a dose-response relationship between sensory effects and
HCHO levels in mobile homes. Data were presented which support a
qualitative relationship. However, it is also important to note
that HUD's study does not address the question of concentration
levels of HCHO in the mobile home and the magnitude of the effect
on the resident.
OSHA has produced an assessment of both noncancer irritant
and cancer effects. For the noncancerous effects assessment,
OSHA relies on data submitted by industry (SOCMA, 1979) and
certain assumptions. SOCMA collected information on nose and eye
irritation from 17 industries where HCHO exposure occurs and
calculated average exposure levels. OSHA only used the endpoint
"nose irritation" in their assessment, which SOCMA defined as the
ability to detect HCHO odor. However, one must assume that odor
recognition correlates with eye, nose, and throat irritation. It
may in some individuals, but not in others. For instance, an
individual may have a high odor threshold (1.5 ppm), but a low
eye irritation threshold. Odor perception (strength) is very
subjective. Consequently, odor recognition and strength should
only be used as qualitative markers that HCHO levels may be in
the range when eye, nose, and throat irritation may occur. Also,
the odor respose is very susceptible to fatigue. Fatigue caused
by low, initial HCHO levels may mask subsequent increases in HCHO
levels, thus further complicating the link between the odor
response and irritation.
8-21
-------
In summary, HUD's and OSHA's approaches provide some
qualitative measure of acute effects from HCHO exposure.
However, these techniques do not determine a true dose-response
relationship. The Andersen and Mulhave study is the only study
that reported a dose-response relationship (Table 8-3). However/
this is a clinical study in which only 16 healthy volunteers were
used. Selective bias may be present and in no way should this
^group be presumed to represent the population at large.
Table 8-4 presents response data over a range of exposures
for three acute endpoints. As can be seen from the table,
reductions in the prevalence of these endpoints from small
changes in HCHO levels, say from 0.4 to 0.1 ppm, are difficult to
quantify with a high degree of certainty given the limitations of
the studies available.
In conclusion, none of the reviewed studies provide adequate
data to quantify population risks for the acute effects of
HCHO. At best, the studies provide a qualitative estimate of
population responses over a wide range of exposure levels.
8-22
-------
Table 8-4. EXPOSURE RAMOFS FOR SELECTED ENDPOINTS
Acute Effect
Exposure Level
Prevelance
Author
ro
u>
Nose- Irritation
Eye Irritation
Coucth and
Wheezinq
0.04-0.09
-------
9. RISK CHARACTERIZATION
This assessment has discussed studies of many effects of
HCHO ranging from the perspective of the chemical's interaction
with proteins and DNA to that of overall acute and chronic
biological responses. It is inferred that within the existing
ranges of exposure of both garment workers and home residents,
all or portions of each population are at risk of one or more
adverse effects. The uncertainties in estimating the numbers of
persons who will have effects of each kind at various levels of
exposure have been discussed at length. This section highlights
conclusions of the hazard identification, dose-response
assessment, and exposure assessment components of the risk
assessment, lays out their strengths, weaknesses, and major
assumptions, along with their associated uncertainties and gives
an overall characterization of the various risks.
9.1. Cancer
Under EPA's proposed cancer risk assessment guidelines, HCHO
has been classified as a Group Bl-Probable Human Carcinogen.
This classification is based on an interpretation of the
available human and animal data which indicate that there is
limited evidence of HCHO carcinogenicity from epidemiologic
studies and a finding of sufficient evidence from animal studies.
HCHO has been found to be carcinogenic (same anatomical site
and type of cancer) in two strains of one species, rats, in two,
2-year multidose studies and in two, 2-year single-dose
studies. Statistically significant numbers of malignant
9-1
-------
neoplasms were seen at one site, nasal cavity, only at about 14
ppm, the highest dose tested. In the CUT 2-year study the first
neoplasms were seen in male rats at month 12 and in female rats
at month 15. The same malignant neoplasms were seen in two male
mice in the CUT 2-year study, at the same site, nasal cavity,
only at the highest dose, about 14 ppnu Although not
statistically significant; these lesions may be biologically
significant due to the rarity of nasal tumors in rodents. In
addition, a small number of benign polypoid adenomas were seen in
rats in the CUT study at all dose levels. Hamsters have been
tested in long-term inhalation studies with negative results.
However, study design limitations compromise the results from
these studies. Other studies suggest that HCHO may have
promotional or cocarcinogenic activity.
The data indicate that HCHO is rapidly metabolized at the
site of contact; the tissues receiving the highest dose which
would be expected to show the greatest neoplastic response are
those at or in close proximity to the site of introduction of the
chemical. The long-term animal studies as well as other tests
are consistent with this observation.
The mutagenic activity of HCHO has been shown in numerous in
vitro tests using procaryotlc and eucaryotic cell lines.
However, HCHO is a weak mutagen in these tests. In vivo tests in
mammals have been negative or equivocal at most.
HCHO is not unique among the chemicals in its structural
class in showing carcinogenic activity in animals. Acetaldehyde,
9-2
-------
as well as a few other aldehydes, have shown carcinogenic
activity in animal tests. The clearest response has been seen
with acetaldehyde which is the closest in structure to HCHO.
Although both HCHO and acetaldehyde cause nasal tumors in
rats, HCHO produced squamous cell carcinomas in the anterior
region of the nasal cavity while acetaldehyde produced
adenocarcinemas in the posterior region. As discussed earlier in
this document, experimental nasal carcinogens vary in the tumor
type, tissue site, and species they affect. Generally, not
enough is known to demonstrate a mechanism or pattern for
prediction of tumor progression, species susceptibility, and cell
type for any particular nasal carcinogen.
Since adequate epidemiologic studies are not available to
estimate cancer risk to humans, high to low dose risk
extrapolation using animal data was done. For that purpose, the
CUT multidose study in rats was used. The estimated upper
bounds for excess lifetime risks range from 3 X 10~4 [Bl] to 1 X
10~-* IBI] for apparel workers and 2 X 10~* [Bl] for mobile home
residents based on HUD's mobile home standard. The risk for
garment workers at the OSHA standard of 3 ppm is 6 X 10~3. Risk
estimates based on benign polypoid adenomas are about an order of
magniture greater for the exposures of concern. The principal
route of exposure is by inhalation which is the same route as in
the animal study used for risk estimation. While the only
statistically significant malignant neoplasm seen in the animal
study was squamous cell carcinoma of the nasal cavity, the
9-3
-------
response in humans may or may not be the same in histology or
site because we are not obliged to breathe through the nose as
are rats. Other kinds of tumors in the respiratory system and
proximate tissues (e.g. the brain) are possible, also possible
are tumors at distant sites.
EPA and the Consensus Conference on Formaldehyde agree that
ifCHQ's noncarcinogenie effects (cell killing, irritation) may
potentiate Its careinogenicity. Reduction of human exposure to a
-, .
level that introduces a margin of human safety from these effects
may accomplish a significant reduction in risk of carcinogenic
effects. Animal studies indicate a NOEL of about 1 ppm for
squamous metaplasia. We also cannot rule out the possibility
that the potentiating effects of HCHO could operate to increase
the risk of persons simultaneously exposed to respiratory
carcinogens. Recent epidemiologic studies suggest a synergism
between wood dust and HCHO exposure.
The cancer dose-response in the animal study used to
estimate human risk is very nonlinear. The Agency has used the
multistage model to mimic the observed responses. In keeping
with the proposed EPA Cancer Assessment Guidelines, the linear
upper 95% CL on the model was used to estimate risks from HCHO
exposuref since experimental and mechanistic information did not
lead us to select an alternative to that procedure. It should be
recognized that the model used is very conservative. Another
aspect of the nonlinearity of the experimental data is that it
introduces a high level of uncertainty into the extrapolation of
9-4
-------
risk to low exposures. For instance, the MLE and 95% UCL derived
risks for apparel workers exposed to 0.17 ppm HCHO are 4 X 10~9
IB1] and 3 X 10~4 [Bl], respectively. The nearly 5 orders of
magnitude difference gives an idea of this uncertainty, in
addition, small changes in the input data, if the response is
very nonlinear, can have a great impact on the extrapolated MLE
estimates.
9.2. Other Effects
Acute effects, irritation of the eyes and upper respiratory
system are the most common HCHO effects. Most persons experience
discomfort within the range of 0.1 to 3 ppm HCHO. The eyes are
generally the most sensitive. For roost persons odor recognition
occurs at about 1 ppm HCHO and can be a marker for acute
effects. More serious effects occur at exposures above 3 ppm.
In addition to its sensory effect on receptors of the eyes,
nose, and throat, HCHO also causes inflammation and cellular and
tissue damage. Experiments in rats and monkeys indicate that
chronic exposures over 1 ppm causes squamous metaplasia and
hyperplasia. Also, subchronic exposures of 2 ppm or greater
affect the mucociliary clearance system, causing mucostasis and
ciliastasis. Ultrastructural changes to cilia may be occurring
below 2 ppm. Possible impairment of the nasal mucociliary system
(and other mucociliary systems of the respiratory system) by HCHO
has been linked to increased episodes of respiratory tract
infections in children.
9-5
-------
A small number of reports associate HCHO with allergic
asthma-like symptoms. However, there are no sufficiently
well-controlled studies to establish whether HCHO is an inhalant
sensitizer.
On the other hand, HCHO is a well-known dermal sensitizer
and irritant. After sensitivity is induced, concentrations which
®iicit allergic response range from as low as 30 ppm in a patch
t@s£ to 60 ppm from actual use of formalin. HCHO causes allergic
contact dermatitis (Type IV allergy) and probably immunologic
contact urticaria (hives or rash) (Type I allergy). Nonallergic
contact urticaria has also been reported from multiple exposure.
HCHO has been associated with a number of central nervous
system (CNS) disturbances such as memory loss, irritability, and
sleep disturbaaces. However, the human studies linking these CNS
effects to HCHO have many technical and design faults which make
the results questionable.
A limited number of reports have suggested that HCHO may
cause reproductive disorders. However, no clear evidence exists
to link HCHO to adverse reproductive outcomes. In addition,
based on the available literature it is not likely that HCHO
poses a risk as a potential human teratogen.
Garment workers and home residents are at risk from HCHO's
acute effects. The HCHO exposures experienced by these two
groups fall within the lower end of the range (0.1 to 3 ppm) •
where most persons experience irritation of the eyes, nose, and
throat. However, the distribution of thresholds within the range
9-6
-------
for the various effects is not known. Attempts to define the
dose-response relationships for these effects have not been
successful. However, it is reasonable to assume that some
fraction of new homeowners will experience discomfort during the
first year of occupancy if adverse temperature and humidity
conditions are allowed to exist in the home. An analysis of
HUD's manufactured home standard indicates that HCHO levels could
approach 1.0 ppm at high temperature and humidity conditions,
which is well within the range that some persons may experience
discomfort. What fraction will respond is unknown.
In addition to sensory effects, HCHO also is capable of
causing cellular changes in the upper respiratory system. Animal
studies have shown that HCHO can inhibit mucociliary action after
only a few days of exposure to 2, 6 or 15 ppm. Also, chronic
studies have shown significant levels of squamous metaplasia in
the nasal cavity of rats at 2.0 ppm and in monkeys exposed to 3.0
ppm. The NOEL for squamous metaplasia is estimated to be 1.0 ppm
during chronic exposure. Disruption of the nasal mucociliary
clearance system (shown in rats at exposures of 2 ppm and
greater) is a significant effect because this system is an
important defense mechanism which helps clear particulate matter
and microbes from the body. The home populations and many
garment workers are expected to experience chronic exposures of
below 0.5 ppm.
9-7
-------
9.3. summary
The effects of HCHO which cause the most public complaint
are irritation of eyes and upper respiratory tract. Cellular
effects may be a factor contributing to carcinogenicity as
previously discussed. These effects may also worsen the
condition of individuals who have other underlying health
problems such as asthma or respiratory tract infections, or
predispose them to such problems, but it is not known how large a
population may be affected. In fact, for none of the several
irritation effects of HCHO are available data sufficiently
reliable to permit their full impact on the population to be
assessed.
Prom the available reports, we can estimate where the range
of thresholds for human response appears to be, but the full
health consequences cannot be characterized since the underlying
health of individuals and the frequency of their exposure are
critical, unknown factors. Table 9-1 summarizes the risks from
the cancer and noncancer hazards of HCHO in the populations of
concern. Cancer risks are presented as individual risk
estimates. For the noncancer effects the margins of safety for
each effect are given for the exposures of concern. As Table 9-1
indicates? the current OSH& standard of 3 ppm presents
&•<-' -.- .-' •>.*;w"'--- .---•- •• • . • .. - :.-y - <-=;-.».. -
potentially very high cancer risks and virtually no margin of
safety for cellular and sensory effects. For garment workers .the
cancer risk ranges from 3 X 10""* to 1 X 10~3 based on carcinoma
data and 5 X 10~3 to 2 X 10~2 based on adenoma data. Small
9-8
-------
SOMUtf Residents
(at HUD Std.
of 0.4 ppn)
(0.15 ppn
10-yr av.)
Carcinoma
Data
UCL 6 X 10"3
MLE 6 X 10"4
UCL 3 X 10"4
NLE 4 X 10~9
UCL 1 X IQ'l
MLE 6 X 10~7
UCL 2 X10"4
MLE 1 X 10~9
Adenona
Data
UCL 1 X 10"1
MLE 2 X10"1
UCL 5 X 10~3
MLE 2 X 10~3
UCL 2 X 10~2
MLE 8 X 10"3
UCL 3 X 10~3
MLE 1 X 10"3
Cellular Eye
Effects Irritation
(tt*l 1 ppn) (0.05-0.5 ppn)*
0.3 0.02-0.2
6 0.3-3
2 0.08-0.8
3 0.1-1
NDoe/ttroat
Irritation
(1-11 ppn)*
0.3-4
6-65
2-17
3-28
Eye/Nose/Throat
Irritation as
reported by
Consensus Wbrkshop
(0.1-3 ppm)*
.03-1
0.6-18
0.2-5
0.3-8
Conventional
Home**
Residents
(0.4 ppn new
hones)
(0.030 long-
term av.)
UCL 3 X 10"4
MLE 7 X 10"12
UCL 4 X 10~3
MLE 2 X 10~3
0.1-1
3-28
0.3-8
*Range of individual thresholds.
**Cancer risk based on 10-year and long-term averages as appropriate. Margins of safety based on HUD
standard and new ham levels as appropriate. HCHO levels higher than 0.4 ppn can be expected due to
adverse temperature/hunidity conditions, i.e. >77°F/50% RH.
-------
margins of safety are present for cellular and sensory effects
except for eye irritation. However, it must be remembered that
tolerance to eye irritation exists. Mobile home residents face
moderate cancer risks and have some margin of safety for all
effects except for eye irritation in some individuals. The
situation is essentially the same for conventional home
^residents* However, as discussed earlier (see Section 6.
Exposure Assessment), temperature and humidity conditions have a
inajor impact on indoor HCHO levels and some fraction of new homes
may experience HCHO levels greater than 0.4 ppm for varying
lengths of time. Consequently, the already small margins of
safety would be gone.
9-10
-------
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