vvEPA
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March 1995
Great Lakes Water
Quality Initiative
Criteria Documents
for the Protection
of Human Health
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Environmental Protection Agency, and approved for publication
as a support document for the Great Lakes Water Quality
Initiative. Mention of trade names and commercial products
does not constitute endorsement of their use.
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GREAT LAKES WATER QUALITY INITIATIVE
HUMAN HEALTH CRITERIA DOCUMENTS
BENZENE 1
CHLORDANE 6
CHLOROBENZENE 10
CYANIDES 14
P,P'-DICHLORODIPHENYLTRICHLOROETHANE (DDT) 19
DIELDRIN 24
2,4-DIMETHYLPHENOL 28
2,4-DINITROPHENOL 31
HEXACHLOROBENZENE 34
HEXACHLOROETHANE- 40
LINDANE 47
MERCURY 50
METHYLENE CHLORIDE 55
POLYCHLORINATED BIPHENYLS (PCBS) 63
2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN (2,3, 7,8-TCDD) 66
TOLUENE 74
TOXAPHENE 78
TRICHLOROETHYLENE 81
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TERMS AND VALUES USED IN THE GREAT LAKES
WATER QUALITY INITIATIVE CRITERIA DOCUMENT
TERM
Human noncancer
criterion/value
Human cancer criterion/value
Acceptable daily exposure
Risk associated dose
Cancer slope factor
Risk level
No observed adverse effect
level
Lowest observed adverse effect
level
Uncertainty factor
Body weight
Relative source contribution
Water consumption - Drinking
water and incidental exposure
Water consumption - Incidental
exposure
Fish consumption trophic level
3 fish
Fish consumption trophic level
4 fish
Bioaccumulation factor for
trophic level 3
Bioaccumulation factor for
trophic level 4'
ABBREV.
H^HI • H^^H • •
HNC/HNV
HCC/HCV
ADE
RAD
ql*
NOAEL
LOAEL
UF
BW
RSC
wcd
wcr
FC^
FC™
BAF^
BAF™
VALUE
Varies by chemical
Varies by chemical
Varies by chemical
Varies by chemical
Varies by chemical
1 x 10'5
Varies by chemical
Varies by chemical
Varies by chemical
70 kg, except 65 kg
for mercury
0.80 noncarcinogens
1.00 carcinogens
2 liters/day
0.01 liter/day
0.0036 kg/day
0.0114 kg/day
Varies by chemical,
expressed as L/kg
Varies by chemical,
expressed as L/kg
Criteria are rounded to two significant figures and are expressed
in ug/L. BAFs are taken from the Technical Support Document for
Bioaccumulation Factors which is available in the docket for the
final Great Lakes Water Quality Initiative.
11
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GREAT LAKES WATER QUALITY INITIATIVE
TIER I HUMAN HEALTH CRITERIA FOR
BENZENE
CAS NO. 71-43-2
Td.gr 1 Human Noncancer Crd.teri.on
Acute exposure to benzene vapors by humans is often
associated with neurotoxicity characterized by loss of sensation,
vertigo, headache and depression of the central nervous system.
Hematopoietic toxicity involving changes in the bone marrow,
spleen, and thymus has been associated with benzene exposure.
Benzene has also been found to cause embryo/fetotoxicity in
experimental animals (EPA, 1980).
There are few chronic or oral studies available which
examine the noncarcinogenic effects of benzene. The subchronic
oral study by Wolf et al. (1956) was considered appropriate for
Tier 1 HNC derivation. In this study, female Wistar rats in
groups of 10 were administered benzene in olive oil by gavage for
5 days/week for six months. A group of 20 rats served as
controls. Dose levels were 0, 1, 10, 50, and 100 mg/kg/bw/day.
During this period hematologic examinations were performed on
selected animals. Growth, body weight, organ weights, behavior,
urea nitrogen in' blood, histopathological changes and bone marrow
counts were also evaluated. Rats exposed to 50 and 100 mg/kg/day
exhibited leukopenia and erythrocytopenia, whereas these effects
were marginal in the 10 mg/kg/day group. The 1 mg/kg/day dose
level was considered the NOAEL for this study. This dose is
equivalent to 0.71 mg/kg/day after being adjusted for exposure
for only 5 days/week.
The findings of the Wolf et al. (1956) study are supported
by the results of a chronic study by NTP (1986). In this study,
C57BL16N mice and F344 rats (50 animals/sex/group) were
administered benzene orally at doses of 0, 50, 100 or 200 mg/kg,
5 days/week, for 103 weeks. An additional group consisting of
female rats and mice of both sexes were administered 25 mg/kg.
Blood was taken for analysis from 10 animals/sex/group at various
times during the study. The results of the study showed dose-
related leukopenia in rats and mice of each sex for the first 18
months of the study. However, at 24 months, the numbers of white
blood cells in high dose male rats, high dose female rats, and
mid-dose male mice were higher than controls. Numbers of white
blood cells in dosed female mice were not significantly different
from controls.
Hematopoietic toxicity of benzene following exposure via
inhalation was reported by Deichmann et al. (1963). In this
study, groups of male and female Sprague-Dawley rats were exposed
5 hours/day, 4 days/week, for periods ranging from 5 weeks to 7
months, to benzene concentrations of 0, 15, 29, 31, 44, 47, 61,
65, or 831 ppm. Several hematologic parameters, and other
parameters including body weight, food intake and blood benzene
-------
levels were determined periodically during the study. Following
2-4 weeks of exposure, groups exposed to benzene concentrations
of 61 to 831 ppmdemonstrated a significantly increased level of
leukopenia. Hematopoietic effects were moderate in groups
exposed to 44 to 47 ppm for 5-8 weeks. Exposure to 31 ppm
benzene for over 4 months did not induce changes in the
hematopoietic system and was considered a NOAEL for this study.
Based on the conditions of exposure and an assumed absorption
factor of 50% (EPA, 1987), a NOAEL of 2.35 mg/kg/day was
calculated. This value is comparable to the value calculated in
the Wolf et al. (1956) study.
EPA (1985) suggested that the Wolf et al. (1956) and Chang
(1972) studies could be used to establish a range of acceptable
daily intake (ADI) values. In the Chang (1972) study 119 workers
occupationally exposed to benzene were examined. Hematological
abnormalities were reported in 28 of the workers. These
abnormalities included 21 workers with anemia, 2 with leukopenia,
and 5 with anemia and leukopenia. Based on an estimate of
exposure duration and benzene concentration, the researcher
derived an exponential function which suggested a threshold level
of 10 ppm for hematologic effects. This study was not used for
criterion development due to the absence of reliable data on the
actual exposure concentrations for the individual employees.
Rozen et al. (1984) examined the effect of inhalation
exposure to 0, 10, 31, 100 and 301 ppm benzene on B- and T-
lymphocyte mitogen-induced blastogenesis in C57B1 mice. Exposure
to benzene at all doses for 6 hours/day for 6 days resulted in a
significant depression in femoral lipopolysaccharide (LPS)-
induced B-colony forming ability while total numbers of B-
lymphocytes were significantly depressed at 100 and 300 ppm.
Splenic phytohemagglufinin {PHA)- induced blastogenesis was
significantly depressed at 31, 100 and 300 ppm while total
numbers of T-lymphocytes were significantly depressed at 100 and
300 ppm. This study was not used for risk assessment because it
used the inhalation route of exposure and it is questionable
whether the effects produced in this study are biologically
significant and adverse.
Few studies using the oral route of exposure have examined
the reproductive/developmental effects of benzene. Nawrot and
Staples (1979) administered 0.3, 0.5 or 1.0 ml/kg/day (790, 1320
and 2640 mg/kg/day, respectively) benzene to pregnant CD-I mice
during days 6-15 or 12-15 of gestation. Despite some maternal
lethality and embryonic resorptions at the two higher doses, no
evidence of teratology was seen.
ADE = NOAEL = 0.71 ma/ka/d = 7.1 x 10"1 mg/kg/d
UF ' 1000
Where: Uncertainty Factor = 1000, composed of:
lOx for interspecies variability
lOx for intraspecies differences
lOx for subchronic exposure duration
-------
Drinking Water Sources:
HNV = _ APE x BW x RSC
WCd + [ (FC^ x BAFro) + (FC™ X
» 7.1 x 10** ma/ka/d x 70 ka x 0.8
2 1/d + [(0.0036 x 3) + (0.0114 x 5)]
= 19 ug/L
Non-Drinking Water Sources:
HNV = _ APE x BW x RSC _
WCr + [ (FCTLj x BAFro) + (FCru X
= _ 7.1 x 10** ma/ka/d x 70 ka x 0.8
0.01 1/d + [{0.0036 x 3) + (0.0114 x 5)]
= 5.1 x 10? ug/L
References :
Chang, I.W. 1972. Study on the threshold limit value of benzene
and early diagnosis of benzene poisoning. J. Cath. Med. Coll.
23:429.
Deichmann, W.B., W.E. MacDonald. and E. Bernal . 1963. The
hematopoietic tissue toxicity of benzene vapors. Toxicol. Appl.
Pharmacol. 5:201-224.
International Agency for Research on Cancer (IARC) . 1982. IARC
Monograph: Evaluation of the Carcinogenic Risk of Chemicals to
Humans, Volume 29, WHO Publications Center, USA, Albany, NY, pp
1-416.
National Toxicology Program (NTP) . 1986. Toxicology and
Carcinogenesis Studies of Benzene in F344/N Rats and B6C3F1 Mice
(Gavage Studies). NTP Technical Report Series. 289., National
Toxicology Program, Research Triangle Park, NC.
Nawrot, P.S. and R.F. Staples. 1979. Embryo- fetal toxicity and
teratogenicity of benzene and toluene in the mouse. Teratology.
19:41a.
Rozen, M.G., C.A. Snyder, and R.E. Albert. 1984. Depressions in
B- and T-lymphocyte mi togen- induced blastogenesis in mice exposed
to low concentrations of benzene. Toxicol. Letters. 20:343-349.
U.S. Environmental Protection Agency (EPA). 1987. Integrated
Risk Information System (IRIS database) . Chemical file for
-------
benzene (CAS No. 71-43-2). Verification Date 10/9/87. Last
Reviewed 10/9/87'.
U.S. Environmental Protection Agency (EPA). 1985. Drinking
Water Criteria Document for Benzene (Final Draft). U.S.
Environmental Protection Agency, PB86-118122. Washington, D.C.
U.S. Environmental Protection Agency (EPA). 1980. Ambient Water
Quality Criteria Document for Benzene. Washington, DC. EPA
440/5-80-018.
Wolf, M.A., V.K. Rowe, D.D. McCollister, R.L. Hollingsworth and
F. Oyen. 1956. Toxicological studies of certain alkylated
benzenes and benzene. A.M.A. Arch. Indust. Health. 14:357-398.
r 1 Human C^T'ocr Criterion
According to the weight -of -evidence method for the
classification of carcinogens, benzene is a Class A carcinogen
(known human carcinogen) (IARC, 1982; EPA, 1987; 1989) . This is
based on sufficient evidence from epidemiologic studies on the
incidence of non-lymphocytic leukemia from occupational exposure,
and increased incidence of neoplasms in rats and mice exposed to
benzene by inhalation and gavage (EPA, 1987) . In addition,
numerous studies have found a significant increase in chromosomal
aberrations of bone marrow cells and peripheral lymphocytes from
workers exposed to benzene (IARC, 1982) . The data are sufficient
to derive a Tier 1 HCC for benzene.
Numerous epidemiologic and case studies have shown a
relationship between leukemia and exposure to benzene (IARC,
1982) . The oral slope factor for benzene based on human data is
estimated to be 2.9E-2 (mg/kg/dayr1 (EPA, 1987). The unit risk
estimate is based on the geometric mean of four maximum
likelihood point estimates using pooled data from the studies of
Rinsky et al. (1981) and Ott et al. (1978), which was then
adjusted for the results from the Wong et al. (1983) study as
described by EPA (1987) .
The slope factor (ql*) of the dose- response curve for the
carcinogenic effects of benzene by the oral route, 2.9E-2
(mg/kg/day) ~l is used in the calculation of the HCC for benzene.
RAD = Risk Level = _ 1 x 1Q-5 _
ql* 2.9 x lO'2 (mg/kg/d)'1
= 3.448 x ID"4 mg/kg/d
Drinking Water Sources:
-------
HCV = _ RAD X BW
WCd + [(FCru x BAFra) + (FC^ x
= _ 3.448 x IP"4 ma/kcr/d x 70 ka
2 1/d + [(0.0036 x 3) + (0.0114 x 5)]
= 12 ug/L
Non-Drinking Water Sources:
HCV = _ RAD X BW _
WCr + [ (FCru x BAF^) + (FC^ x
= _ 3.448 x 10"* ma/ka/d x 70 ka
0.01 1/d + [(0.0036 x 4} + (0.0114 x 5)]
= 3.1 x 10? ug/L
References :
International Agency for Research on Cancer (IARC) . 1982. IARC
Monograph: Evaluation of the Carcinogenic Risk of Chemicals to
Humans, Volume 29, WHO Publications Center, USA, Albany, NY, pp
1-416.
Ott, M.G., J.C. Townsend, W.A. Fishbeck and R.A. Langner. 1978.
Mortality among individuals occupationally exposed to benzene.
Arch. Environ. Health., 33: 3-10.
Rinsky. R.A. , R.J. Young and A.B. Smith. 1981. Leukemia in
benzene workers. Am. J. Ind. Med. 2: 217-245.
U.S. Environmental Protection Agency (EPA). 1987. Health
Effects Assessment for Benzene. EPA/600/8-89/086. Cincinnati,
OH.
U.S. Environmental Protection Agency (EPA) . 1987. Integrated
Risk Information System (IRIS database) . Chemical file for
benzene (CAS No. 71-43-2). Verification Date 10/9/87. Last
Reviewed 10/9/87.
U.S. Environmental Protection Agency (EPA) . 1980. Ambient Water
Quality Criteria Document for Benzene. Washington, DC. EPA
440/5-80-018.
Wong, 0., R.W. Morgan and M.D. Wharton. 1983. Comments on the
NIOSH study of leukemia in benzene workers. Technical report
submitted to Gulf Canada, Ltd., by Environmental Health
Associates.
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GREAT LAKES WATER QUALITY INITIATIVE
TIER I HUMAN HEALTH CRITERIA FOR
CHLORDANE
CAS NO. 57-74-9
n NoncBncoir Criterion
A review of the available literature indicates that the most
appropriate study for HNC derivation for chlordane is a study
conducted by Velsicol Chemical Corporation (1983a) . In this
study, 80 Fischer 344 rats of each sex were administered 0, 1, 5
or 25 ppm chlordane for 130 weeks. Hematological , biochemical,
urinary and pathplogical measurements were made on eight
animals/sex/group at weeks 26 and 52. The same measurements were
made on animals which survived to week 130. Liver hypertrophy
occurred in females at 5 ppm (0.273 mg/kg/d) and a NOEL of l ppm
(0.055 mg/kg/d) was determined. No liver lesions were found in
male rats and a NOEL of 25 ppm (0.1175 mg/kg/d) was determined.
The NOEL for female rats is slightly lower than the NOELs
determined for mice and dogs. A 24 -month chronic study in ICR
mice found NOELs of 0.123 mg/kg and 0.138 mg/kg for male and
female mice, respectively (Velsicol, 1983b) . A study using
Beagle dogs found NOELs of 0.06 mg/kg and 0 . 09 mg/kg for male and
female dogs, respectively (Wazeter, 1967) .
Data on the reproductive and developmental effects of
chlordane are limited. ATSDR (1989) cited a study by Usami et
al. (1986) which showed no malformations in pups whose dams were
administered 20, 40 or 80 mg/kg/d chlordane from day 7 to 17 of
gestation. The finding of this study suggests that exposure
levels which may cause adverse effects on development are higher
than the NOEL cited above for the Velsicol study (1983a) . Other
studies reported by Chernoff and Kavlock (1982) and Ingle (1952
as cited by EPA, 1990) also indicate that criteria derived from
the chronic NOAEL of 0.055 mg/kg/d (Velsicol, 1983a) should be
protective of potential developmental effects.
The quality of the Velsicol (1983a) rat study was deemed
sufficient to derive a Tier 1 HNC. This study was also used by
EPA (1989; 1990) to derive the oral RfD for chlordane. The HNC
was derived from the female rat NOEL using an uncertainty factor
of 1000 to account for interspecies variability (10) and
intraspecies differences (10) and an additional uncertainty
factor of 10 to account for the lack of an adequate reproduction
study and adequate chronic study in a second mammalian species
and the generally inadequate sensitive endpoints studied in
existing studies.
ADE = NOAEL = 5.5 x IP'2 mg/ka/d = 5.5 x 10'5 mg/kg/d
UF 1000
Where: Uncertainty Factor = 100, composed of:
-------
lOx for interspecies variability
lOx for intraspecies differences
lOx to account for lack of adequate reproduction study
Drinking Water Sources:
HNV = _ APE x BW x RSC _
WCd + [{FCro x BAF^) + (FCru x
5.5 x IP'5 mo/ka/d x 70 ka x 0.8
2 1/d + [{0.0036 x 116,600) + (0.0114 x 154,200)]
= 1.4 x 10'3 ug/L
Non-Drinking Water Sources:
HNV = _ APE x BW x RSC _
WCr + [ (FCrL3 x BAFTLS) + (FC^ x BAF^) ]
- _ 5.5 x IP'5 ma/ka/d x 70 ka x 0.8 _
0.01 1/d + [(0.0036 x 116,600) + (0.0114 x 154,200)3
= 1.4 x 10'3 ug/L
References :
Agency for Toxic Substances and Disease Registry (ATSDR) .
1989. Toxicological Profile for Chlordane. Department of Health
and Human Services. U.S. Public Health Service.
Chernoff, N. and' R. J. Kavlock. 1982. An in vivo
teratology screen utilizing pregnant mice. J. Toxicol. Environ.
Hlth. 10:541-550.
Ingle, L. 1952. Chronic oral toxicity of chlordane to
rats. Arch.Ind. Hyg. Occup. Med. 6:357-367.
U.S. Environmental Protection Agency (EPA). 1989.
Integrated Risk Information System (IRIS database) . Chemical
file for chlordane (57-74-9). Verification Date 3/22/89. Last
Revised 7/1/89.
U.S. Environmental Protection Agency (EPA) . 1990. Drinking
Water Criteria Document for Heptachlor, Heptachlor Epoxide and
Chlordane. Revised November, 1990. ECAO-CIN-406.
Usami, M. , K. Kawashima, S. Nakaura, et al. 1986. Effects of
chlordane on prenatal development of rats. (Abstract) . Eisei
Shikenso Hokoku. 104:68-73.
-------
Velsicol Chemical Corporation. 1983a. Yonemura, T., F.
Takamura and Y. Takahashi. Thirty-month chronic toxicity and
tumorigenicity test in rats by chlordane technical. (Unpublished
study by Research Institute for Animal Science in Biochemistry
and Toxicology, Japan).
Velsicol Chemical Corporation. 1983b. Inui, S., K.
Yamazaki, T. Yonemura, et al. Twenty-four month chronic toxicity
and tumorigenicity test in mice by chlordane technical.
(Unpublished study by Research Institute for Animal Science in
Biochemistry and Toxicology, Japan).
Wazeter, F.X. 1967. Two-Year Chronic Feeding Study in the
Beagle Dog. Sponsored by Velsicol Chemical Corporation
(Unpublished).
Tier 1 Human Cancer Criterion
There are inadequate data available to determine whether
chlordane is a human carcinogen (EPA, 1987; 1990). Chronic
studies using four strains of mice (CD-I, B6C3F1, C5781/6N, ICR)
of both sexes have shown an increase in the occurrence of liver
tumors. Additional weight-of-evidence for chlordane's
carcinogenicity is provided by its structural similarity to other
compounds (i.e., dieldrin and heptachlor) which have been found
to induce hepatocellular carcinomas in mice. The results of
various mutagenicity studies are inconclusive as to this
chemical's ability to cause mutagenic effects. The weight-of-
evidence for chlordane carcinogenicity is sufficient for B2
(probable human carcinogen) classification (EPA, 1986; 1987;
1990) . The data4 are sufficient to derive a Tier 1 HCC.
Two key studies (NCI, 1977; Velsicol, 1973 as cited in EPA,
1986) found a significant increase in hepatocellular carcinomas
in treatment groups when compared to controls. Both studies also
showed a dose-response relationship between exposure of mice to
chlordane and the occurrence of liver tumors. EPA (1986; 1987;
1990) calculated four separate slope factors from these key
studies, and derived a recommended slope factor of 1.3 (mg/kg/d)"
from the geometric mean of these slope factors. This method of
computing a slope factor is used "in situations where no single
study is judged most appropriate, yet several studies
collectively support the estimate ..." (EPA, 1989). According
to EPA (1989), the advantage of this method of determining the
slope factor is that all relevant data are used in the
computations.
RAD = Risk Level = 1 x IP'5 = 7.69 x 10* mg/kg/d
ql* . 1.3 (mg/kg/d)-1
-------
Drinking Water Sources:
HCV = _ RAD x BW _
WCd + [(FCTL3 x BAFra) + (FC™ x BAP™)]
7.69 x IP"6 mcr/ka/d x 70 ka
2 1/d + [(0.0036 x 116,600) + (0.0114 x 154,200)]
- 2.5 x 10-* ug/L
Non-Drinking Water Sources:
HCV = _ RAD x BW _
WCr + [(FCru x BAF^) + (FC^ x
= _ 7.69 x IP"6 ma/ko/d x 70 kg _
0.01 1/d + [(0.0036 x 116,600) + (0.0114 x 154,200)]
= 2.5 x 10" ug/1
References :
National Cancer Institute (NCI) . 1977. Bioassay of
Chlordane for possible car cinogeni city. NCI Carcinogenesis Tech.
Rep. Ser. No. 8. U.S. DHEW Publ . No. (NIH) 77-808. Bethesda, MD.
U.S. Environmental Protection Agency (EPA). 1986.
Carcinogenicity Assessment of Chlordane and Heptachlor/Heptachlor
Epoxide. Carcinogen Assessment Group. Office of Health and
Environmental Assessment, Washington, DC.
U.S. Environmental Protection Agency (EPA). 1987. Integrated
Risk Information System (IRIS database) . Chemical file for
chlordane (57-74-9) . Verification Date 4/1/87. Last Revised
1/1/91.
U.S. Environmental Protection Agency (EPA). 1989. Risk
Assessment Guidance for Superfund. Volume 1. Human Health
Evaluation Manual (Part A). Interim Final. OERR. EPA/540/1-
89/002.
U.S. Environmental Protection Agency (EPA). 1990. Drinking
Water Criteria Document for Heptachlor, Heptachlor Epoxide and
Chlordane. Revised November, 1990. ECAO-CIN-406.
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GREAT LAKES WATER QUALITY INITIATIVE
TIER 1 HUMAN HEALTH CRITERIA FOR
CHLOROBENZENE
CAS NO. 108-90-7
Tier 1 H"mar| Nonc&ncer Criterion
A review of. the available literature indicates inadequate
human data for quantitative risk assessment of chlorobenzene
based on human health effects. Humans exposed occupationally to
chlorobenzene intermittently for up to 2 years displayed signs of
neurotoxicity including numbness, cyanosis (from depression of
the respiratory center), hyperesthesia and muscle spasms
(Rozenbaum, 1947, as cited in ATSDR, 1990). While these findings
provide qualitative evidence that chlorobenzene is potentially
neurotoxic, specific exposure levels are not available to support
quantitative risk assessment.
Several animal studies were identified during a review of
the available literature. The most appropriate basis for HNV
derivation for chlorobenzene is the NOAEL from a subchronic dog
study by Monsanto Company (1967). Young adult pure-bred beagle
dogs (4/sex/group) were administered chlorobenzene in gelatin
capsules, 5 days/week at doses of 0, 0.025, 0.050 and 0.250
ml/kg/day (converted per EPA (1989a) to 0, 27.25, 54.5 and 272.5
mg/kg/day, respectively) for 13 weeks. Four high-level dogs died
or were sacrificed in moribund condition between the third and
fourth weeks of the study. These deaths were preceded by
anorexia, decreased activity, body weight loss, cachexia and
coma. The four surviving high-level dogs exhibited temporary
lack of appetite and body weight loss. Changes in hematology,
clinical chemistry and urine analyses were observed at the high
dose. Pathologic changes in the liver, kidney, gastrointestinal
mucosa, and hematopoietic tissue were also observed in high-dose
animals. At 54.5 mg/kg/day, slight hepatic alterations were
observed, and severe cellular variations in the epithelium of the
terminal proximal tubule in the kidney were also observed. The
NOAEL and LOAEL for this study were 27.25 and 54.5 mg/kg/day,
respectively.
The database is judged to be sufficient for Tier 1 HNC
derivation. The key study (Monsanto, 1967) provides a subchronic
NOAEL which is supported by the following additional data.
In a rat study performed by Monsanto Company and abstracted
by Knapp et al. (1971), significant elevations were noted in
liver and kidney' weights of rats administered dietary levels of
100 and 250 mg/kg/day for 93 to 99 consecutive days. No
remarkable histopathologic findings were reported. In addition,
no effects were noted among rats receiving 12.5 or 50 mg/kg/day.
The NOAEL and LOAEL for this study were 50 and 100 mg/kg/day,
respectively (EPA, 1989a). The authors concluded that in
comparison to rats, dogs displayed a greater sensitivity to
chlorobenzene toxicity.
10
-------
In a chronic study by the National Toxicology Program (NTP,
1985), groups of F344/N rats and B6C3F1 mice (50/sex/dose) were
administered chlorobenzene by gavage in corn oil 5 days/week for
103 weeks. The male and female rats received 0, 60 or 120
mg/kg/day; the female mice received 0, 60 or 120 mg/kg/day and
the male mice received 0, 30 or 60 mg/kg/day. A statistically
significant decrease in the survival of high-dose male rats was
observed. Histological examination of the liver showed
hepatocellular necrosis, graded as minimal to mild, in all
groups. In male mice, mortality at both dose levels was
increased to a statistically significant level. No other
chlorobenzene-related clinical toxicity was observed in mice.
Several reproductive and developmental studies have been
performed with chlorobenzene. John et al. (1984) exposed Fischer
344 rats and New Zealand White rabbits by inhalation to
chlorobenzene for 6 hours/day at doses of 0, 75, 210 or 590 ppm
during periods of major organogenesis. Exposure to 590 ppm
caused elevated liver weights in both species and decreased body
weight gain and feed consumption in rats. The developmental
NOAEL was 590 ppm for both species (equivalent to 216 mg/kg/day
for rats and 125 mg/kg/day for rabbits, as per EPA, 1989a). The
maternal NOAELs were 210 ppm (equivalent to 77 mg/kg/day, as per
EPA, 1989a) for rats and 75 ppm (equivalent to 16 mg/kg/day, as
per EPA, 1989a) for rabbits.
In a two-generation reproduction inhalation study in rats
(Nair et al., 1987) groups of 30 male and 30 female Sprague-
Dawley CD rats (F0 generation) were exposed to chlorobenzene at
target concentrations of 0, 50, 150 or 450 ppm for 10 weeks prior
to mating and during mating, gestation, and lactation. Groups of
30 male and 30 female Fl animals were exposed to the same
concentrations of chlorobenzene as the F0 parents, initiated 1
week postweaning and lasting through mating, gestation and
lactation. Hepatocellular hypertrophy and renal changes were
observed among F0 and Fj male rats exposed to 150 and 450 ppm but
exposure of rats to chlorobenzene at levels of 50, 150 or 450 ppm
did not have any adverse effects on reproductive performance or
fertility of male and female rats. A reproductive NOAEL of 165
mg/kg/day and a systemic NOAEL of 18 mg/kg/day (conversions were
from EPA, 1989a) were determined from this study.
The HNV is derived from the NOAEL dose of 27.25 mg/kg/day
(converted to 19.46 mg/kg/day for 5 days/week administration)
from the 13-week- dog study by Monsanto Company (1967) with an
uncertainty factor of 1000. Data from other studies (John et
al., 1984; Nair et al., 1987) suggest that this value will be
protective of reproductive/developmental effects. This approach
is consistent with the risk assessment of chlorobenzene for the
derivation of the oral RfD, drinking water equivalent level
(DWEL), and maximum contaminant level goal (MCLG) by EPA
(EPA,1989a; EPA, 1989b; EPA, 1989C).
11
-------
ADE - NOAEL = 19.46 ma/kcr/d - 1.946 x 10'2 mg/kg/d
UF 1000
Where: Uncertainty Factor « 1000, composed of:
lOx for interspecies variability
lOx for intraspecies differences
lOx for subchronic exposure duration
Drinking Water Sources:
HNV = _ ADE x BW x RSC _
WCd + [(FCnj x BAF-nj) + (FC^ x
= 1.946 x IP'2 mcr/ka/d x 70 ko x 0.8
2 1/d + [(0.0036 x 15) + (0.0114 x 24)]
= 4.7 x 102 ug/L
Non-Drinking Water Sources:
HNV . _ ADE x BW x RSC _
WCr + [ (FCpLj x BAFra) + (PC™ x
= _ 1.946 x IP'2 ma/ka/d x 70 ka x 0.8
0.01 1/d + [(0.0036 x 15) + (0.0114 x 24)]
= 3.2 x 103 ug/L
References :
Agency for Toxic Substances and Disease Registry (ATSDR) . 1990.
Toxicological Profile for Chlorobenzene. U.S. Public Health
Service. ATSDR/TP-90/06.
John, J.A. , W.C. Hayes, T.R. Hanley, Jr., K.A. Johnson. T.S.
Gushow and K.S. Rao. 1984. Inhalation teratology study on
monochlorobenzene in rats and rabbits. Toxicol. Appl . Phannacol.
76(2) :365-373.
Knapp, Jr., W.K., W.M. Busey, and W. Kundzins. 1971. Subacute
oral toxicity of monochlorobenzene in dogs and rats. Toxacol.
Appl. Pharmacol. 19:393.
Nair, R.S., J.A. Barter, R.E. Schroeder, A. Knezevich, and C.R.
Stack. 1987. A two- generation reproduction study with
monochlorobenzene vapor in rats. Fund. Appl. Toxicol. 9 (4): 678-
686.
National Toxicology Program (NTP) . 1985. Toxicological and
Carcinogenesis Studies of Chlorobenzene in F344/N Rats and B6C3F1
12
-------
Mice (Gavage Studies) . NTP-TR No. 261, NIH Publication No. 86-
2517.
Rozenbaum, N.D., R.S. Blekh, S.N. Kremneva, et al. 1947. [Use
of chlorobenzene as a solvent from the standpoint of industrial
hygiene.] Gig. Sanit. 12:21-24. (Russian) As cited in ATSDR
(1990) .
U.S. Environmental Protection Agency (EPA) . 1989a. Integrated
Risk Information System (IRIS database) . Chemical file for
chlorobenzene (108-90-7). Verification Date 1/19/89. Last
Reviewed 1/19/89.
U.S. Environmental Protection Agency (EPA) . 1989b.
Monochlorobenzene . 54 FR No. 97. pp. 22087-22088. May 22, 1989
U.S. Environmental Protection Agency (EPA) . 1989c. Health
Effects Assessment for Chlorobenzene. PB90-142514/XAD. EPA/60/8-
89/099
TJ.63T i TTTman Cancer CrJ.t63TJ.on
Chlorobenzene is not considered carcinogenic.
13
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GREAT LAKES WATER QUALITY INITIATIVE
TIER 1 HUMAN HEALTH CRITERIA FOR
CYANIDES
CAS NO. 57-12-5
Tir 1 HuTnnn nr C3TJ.tsri.on
A review of the available literature indicates inadequate
human data for quantitative risk assessment of cyanides based on
human health effects. Qualitative data suggest that chronic
dietary exposure to naturally occurring cyanogens in cassava
results in thyroid abnormalities in African countries where
cassava is a staple crop. Effects seen, including endemic
goiter, cretinism and congenital hypothyroidism, were potentiated
by low iodine intake and other dietary deficiencies. Tropical
ataxic neuropathy has also been linked to chronic cyanide
ingestion from cassava derivatives (Njoh, 1990) . However, these
data do not provide a dose-response relationship (EPA, 1985a;
1985b; ATSDR, 1988; Njoh, 1990).
From animal studies on the chronic oral toxicity of
inorganic salts of cyanide, the most appropriate basis for HNV
derivation for cyanides is the NOAEL from the chronic rat feeding
study of Howard and Hanzal (1955) . Weanling rats (10/sex/group)
were offered food fumigated with hydrogen cyanide at dietary
concentrations of 100 and 300 ppm HCN, averaging 73 and 183 mg
ClT/kg diet) for two years. Dose levels were approximately 4.6
or 10.8 mg ClT/kg bw/day to females, and 3.6 or 7.5 mg CN"/kg
bw/day to males (EPA, 1985b, 1990) . At termination,
hematological values were within normal limits and neither gross
nor microscopic examination of tissues (including thyroid)
revealed evidence of pathology due to exposure in any of the
exposure groups. Therefore, the NOAEL from this study is 10.8 mg
CN*/kg bw/day.
The database is judged to be sufficient for Tier 1 HNC
derivation. The key study (Howard and Hanzal, 1955) provides a
chronic NOAEL which is supported and supplemented by other data.
In a chronic study (Philbrick et al., 1979), ten male
weanling rats were given 1500 ppm potassium cyanide in the diet
for 11.5 months. The administered dose was approximately 75 mg
KCN/kg bw/day, or 30 mg CNVkg bw/day (ATSDR, 1988; EPA, 1985a;
1985b) . The cyanide exposure in rats receiving either normal or
restricted diet resulted in reduced body weight gain, decreased
thyroid gland activity and increased thyroid weights.
In a study by Tewe and Maner (1981b) , pregnant Yorkshire
pigs (6/dose group) were fed fresh cassava diets containing 0,
276 or 521 mg cyanide (added as KCN) per kg of fresh cassava
offered during gestation and parturition. On the 110th day of
gestation, two gilts per dose group were sacrificed and the
fetuses were evaluated. The remaining gilts in each dose group
were allowed to naturally deliver and were then maintained on a
14
-------
diet with no cyanide throughout the 56-day lactation period. No
serious interference was observed with the production of the
first litter of offspring by gilts receiving cassava diets
containing up to 521 ppm added cyanide during gestation. Gilts
in the high dose group, exhibited possible adverse effects on the
thyroid (increased weight) and kidney (proliferation of
glomerular cells). The high exposure level also suggests a LOAEL
for developmental effects, as the 110-day-old fetuses had
decreased relative spleen, thyroid and heart weights. The
evidence that the thyroid may be a sensitive target organ in pigs
lends support to the thyroid effects reported by Jackson (1988;
see later discussion). However, data interpretation is difficult
due to the small number of gilts evaluated (2/dose group). The
administered levels of 276 and 521 ppm CN~ in the diet convert to
7.7 and 17 mg ClT/kg bw/day for the gilts, using the reported
animal body weights and food intake from the study. The NOAEL
for this study was 276 ppm CN~ in the diet, or approximately 7.7
mg CNYkg bw/day.
Another developmental study (Tewe and Maner, 1981a) reports
that 500 ppm KCN administered in the diet to rats resulted in a
decreased protein efficiency ratio among offspring during the
postweaning growth phase. The dose level has been converted to
approximately 50 mg CIT/kg/day assuming a 10% food conversion
factor (ATSDR, 1988), or approximately 10.6 mg CN~/kg/day per EPA
(1985b).
Other available oral studies are more limited in design,
including the only relevant study with drinking water exposure.
Palmer and Olson' (1979) gave 7 male Sprague-Dawley rats 200 mg/1
KCN in water (or 80 mg/1 CN~; 10 mg CN"/kg/day per EPA, 1985a) or
200 ppm KCN in diet (80 mg CIT/kg food; 8 mg CNYkg/day per EPA,
1985a) for 21 days. At the end of the study, the only parameters
evaluated were body weight and liver weight. Liver weights were
increased over controls following drinking water exposure only.
Although inadequate for criteria derivation, this study suggests
that cyanide via drinking water is more potent for inducing
effects than feeding studies, but is less potent than gavage
exposures.
In another noteworthy but limited study, the effects of oral
cyanide on glucose metabolism, thyroid function and an array of
behavioral indices were evaluated in miniature pigs (Jackson,
1988). Three swine/dose group (mixed sexes) received 0, 0.4, 0.7
or 1.2 mg CN~/kg/day by intraoral bolus as KCN in aqueous
solution, daily for 24 weeks. The author reports that treatment
resulted in a dose-related increase in the fasting blood glucose
level, dose-related decreases in T3 and T4 thyroid hormones, and
numerous altered behaviors. By Chi-square analyses these changes
were determined to be significant, even in the low exposure group
with regard to some parameters. The alterations noted were more
pronounced in the high-dose group, particularly for thyroid
hormone levels, the parameter most clearly indicative of adverse
effects. Suppression of T3 and T4 was dose-related with a much
15
-------
stronger response in the high-dose group (roughly double the
effect seen in the mid-dose group at 24 weeks). However, the
limitations of the study design and reporting are substantial
(Papa, 1990, personal communication). Some of the most critical
deficiencies in design or reporting include: small animal numbers
per group; lack of body weight and organ weight data; exposure
pattern as a single daily bolus dose; unclear biological
significance of the reported biochemical effects; no report of
the variance about the mean for T3, T4, and blood glucose values;
and the distribution of sexes among the four groups was not
reported. The latter point appears critical because from the 12
animals distributed evenly among the four groups, five were
females, and seven were castrated males. The castrated males
were, therefore, unevenly represented among the groups and the
castration effect on thyroid levels and behavior is likely to be
significant (Papa, 1990, personal communication).
The 2-year dietary exposure study by Howard and Hanzal
(1955) has been selected as the key study for the derivation of
the risk assessment of cyanide in drinking water by EPA (1985a,
1985b, 1990). Those assessments have applied an additional
uncertainty factor of 5 due to the dietary method of exposure.
This is intended to account for the relative tolerance to cyanide
when it is ingested with food rather than when it is ingested in
drinking water. The value of 5 was based on an evaluation of
cyanide-binding affinity of food and the GI absorption of cyanide
in food versus drinking water by Dr. Ernest Foulkes of the
University of Cincinnati who served as an external reviewer for
EPA (1985a) (Papa, 1990, personal communication). This 5-fold
(or 20%) adjustment factor for differential bioavailability
between cyanide in feed and in drinking water is concluded to be
appropriate and scientifically supportable in a more recent
analysis (Pearsall and Chrostowski, 1990).
The HNC is therefore derived from the HNOAEL dose of 10.8 mg
CNVkg/day in rat:s via feed (Howard and Hanzal, 1955) , and an
uncertainty factor of 500.
ADE - NOAEL = 10.8 ma CNVka/d = 2.16 x 10"2 mg/kg/d
UP 500
Where: Uncertainty Factor = 500, composed of:
lOx for interspecies variability
lOx for intraspecies differences
5x adjustment for bioavailability,
feed vs. drinking water
Drinking Water Sources:
HNV = ADE x BW x RSC
WCd + [(FCTL3 x BAF-nj) + (FC™ x
16
-------
- 2.16 x IP'2 mcr/ka/d x 70 ka x 0.8
2 1/d + [(0.0036 x 1) + (0.0114 x 1) ]
- 6.0 x 102 ug/L
Non-Drinking Water Sources:
HNV - _ APE x BW x RSC _
WCr + [ (FCrLa x BAF-ru) + (FC^ x
- 2.16 x IP'2 ma/kcr/d x 70 ka x 0.8
0.01 1/d + [(0.0036 x 1) + (0.0114 x 1)]
= 4.8 x 104 ug/L
Note: BAF = 1 by default.
References :
Agency for Toxic Substances and Disease Registry (ATSDR) . 1988.
Toxicological Profile for Cyanide. U.S. Public Health Service.
ATSDR/TP- 88/12.
Howard, J. and R-. Hanzal. 1955. Chronic toxicity to rats of
food treated with hydrogen cyanide. J. Agric. Food Chem. 13:325-
329.
Jackson, L. 1988. Behavioral effects of chronic sublethal
dietary cyanide in an animal model: implications for humans
consuming cassava (Manihot esculenta) . Human Biology 60(4):597-
614.
Njoh, J. 1990. -Tropical ataxic neuropathy in Liberians. Trop.
Geogr. Med. 42(l):92-94.
Palmer, I. and 0. Olson. 1979. Partial prevention by cyanide of
selenium poisoning in rats. Biochemical Biophysical Research
Comm. 90(4) :1379-1386.
Papa, L. 1990. U.S. EPA, ORD, Research Physiologist. Personal
communication with R. Sills, Michigan Department of Natural
Resources .
Pearsall, L. and P. Chrostowski. 1990. The oral bioavailability
of cyanide. Unpublished report. Prepared by Clement Assoc.,
Inc., for Boston Gas Co., Boston MA.
Philbrick, D. et al. 1979. Effect of prolonged cyanide and
thiocyanate feeding in rats. J. Toxicol. Env. Health 5:579-592.
17
-------
Tewe, 0. and J. Maner. I981a. Long-term and carry-over effect
of dietary inorganic cyanide (KCN) in the life cycle performance
and metabolism of rats. Toxicol. Applied Pharmacol. 58:1-7.
Tewe, 0. and J. Maner. 1981b. Performance and
pathophysiological changes in pregnant pigs fed cassava diets
containing different levels of cyanide. Res. Vet. Sci. 30(2):
147-151.
U.S. Environmental Protection Agency (EPA) . 1985a.
Water Criteria Document for Cyanide. Final Draft.
600/X-84-192-1. PB 86-117793.
Drinking
NTIS. EPA-
U.S. Environmental Protection Agency (EPA) . 1985b. Integrated
Risk Information System (IRIS database). Chemical file for
Cyanide, free (57-12-5). Verification Date 8/5/85. Last
Reviewed 8/5/85.-
U.S. Environmental Protection Agency (EPA). 1990. Federal
Register 55 (143):30370-30448. July 25, 1990. National Primary
and Secondary Drinking Water Regulations; Synthetic Organic
Chemicals and Inorganic Chemicals. Proposed Rule.
er 1
Cancer Criterion
Cyanides are not considered carcinogenic
18
-------
GREAT LAKES WATER QUALITY INITIATIVE
'TIER I HUNAN HEALTH CRITERIA FOR
P,P'-DICHLORODIPHENYLTRICHLOROETHANE (DDT)
CAS NO. 50-29-3
Tier 1 Hunmn MoncaTiceir Criterion
A review of the available literature indicates that the most
appropriate basis for HNC derivation for DDT is the NOAEL from
the subchronic rat feeding study of Laug et al. (1950). Weanling
rats (15 /sex/group) were fed commercial -grade DDT (81% p,p'-DDT,
19% o,p'-DDT) at levels of 0, 1, 5, 10 or 50 ppm for 15-27 weeks.
The critical toxic effect was liver toxicity, demonstrated as
relatively mild dose -dependent histopathologic changes in
hepatocytes at doses of 5 ppm and higher. These included
hepatocellular hypertrophy, increased cytoplasmic oxyphilia, and
peripheral basophilic cytoplasmic granules. The NOEL was 1 ppm,
or 0.05 mg/kg bw/day assuming a food consumption rate of 5% body
weight per day. The LOAEL was 5 ppm (0.25 mg/kg bw/day) .
The database is judged to be sufficient for Tier 1 HNC
derivation. The key study (Laug et al., 1950) provides a
subchronic (greater than 90 day) NOEL which is supported and
supplemented by other data. In a 2 -year rat dietary exposure
study (Fitzhugh, 1948) rats were exposed to 10-800 ppm DDT in
feed, resulting in liver lesions at all dose levels with a LOAEL
of 10 ppm (0.5 mg/kg bw/day). The available mammalian
reproduction and. developmental studies of DDT indicate that an
HNC derived from the critical effect of liver toxicity will be
protective of potential human reproductive/ developmental effects
(EPA, 1985) . The HNC is based on the subchronic rat NOEL of 0.05
mg/kg bw/day, with a total uncertainty factor of 100. An
uncertainty factor for subchronic exposure duration is not
included because of the corroborating chronic study in the
database. This approach is consistent with the oral RfD
development by EPA (1985) .
•
ADE = NQAEL = 0.05 ma/kcr/d = 5.0 x 10"4 mg/kg/d
UF 100
Where: Uncertainty Factor = 100, composed of:
lOx for interspecies variability
lOx for intraspecies differences
Drinking Water Sources:
HNV = _ ADE x BW x RSC _
x BAFro) + (PC™ x
19
-------
5 x 10"* ma/ka/d x 70 ka x 0.8
2 1/d + [(0.0036 x 376,400) + (0.0114 x 1,114,000)]
- 2.0 x ID'3 ug/L
Non-Drinking Water Sources:
HNV = _ APE x BW x RSC _
WCr + [ (FCnj x BAF^) + (FC^ x
5 x IP"4 ma/ka/d x 70 ka x 0.8
0.01 1/d + [(0.0036 x 376,400) + (0.0114 x 1,114,000)]
- 2.0 x 10"3 ug/L
References :
Fitzhugh, 0. 1948. Use of DDT insecticides on food products.
Industrial and Engineering Chemistry. 40 (4) :704-705.
Laug, E., A. Nelson, O. Fitzhugh and F. Kunze. 1950. Liver cell
alteration and DDT storage in the fat of the rat induced by
dietary levels of 1-50 ppm DDT. J. Pharmacol. Exp. Therap.
98:268-273.
U.S. Environmental Protection Agency (EPA). 1985. Integrated
Risk Information System (IRIS) . Chemical file for DDT (50-29-3) .
Verification Date 12/18/85. Last Revised 9/30/87.
Tier 1 Hi,"n;*r| Cancer Criterion
A review of the available literature for DDT car cinogeni city
reveals a lack of adequate epidemiological data and an extensive
database of chronic oral rodent bioassays . These studies
indicate that the induction of liver tumors is the most
consistent and significant tumorigenic response to DDT in
rodents. EPA (1987) has classified the weight of evidence of DDT
carcinogenicity as B2 based on multiple positive studies in two
species (mice and rats) , with ancillary evidence including
promoting activity, genotoxicity, and structural relation to
other rodent liver carcinogens. Therefore, the data are
sufficient for Tier 1 HCC derivation.
The animal bioassay providing the highest slope factor
estimation is the multigeneration mouse feeding study of Tar j an
and Kemeny (1969) . The predominant tumor types were leukemias
and lung tumors; a significant liver response was not seen. EPA
(1980) derived ambient water quality criteria from the slope
factor of 8.422 (mg/kg/day) " from this study.
EPA (1986a) evaluated the carcinogenicity of DDT and other
related compounds and determined that the Tar j an and Kemeny
20
-------
(1969) study was not the most appropriate basis for quantitative
risk assessment. The study's findings were not consistent with
the numerous other positive bioassays in terms of the organ site
(lung/leukemia versus liver) and the slope factor (about an order
of magnitude greater) . This slope factor was judged to be a
statistical outlier in relation to the liver tumor induction data
from six key studies, and the quality and validity of the study
was also questionable. EPA (1986a) derived a slope factor from
the consistent finding of liver tumor induction in rats and mice,
for which the six key studies provided slope factors within a 13 :
fold range. The recommended slope factor of 3.4 E-l (mg/kg/day) "
was derived as the geometric mean of ten slope factors from
those six studies (Turusov et al., 1973; Terracini et al., 1973;
Thorpe and Walker, 1973; Tomatis and Turusov, 1975; Cabral et
al., 1982; Rossi et al., 1977). The averaging procedure was
followed because no further database refinement or rejection
could be logically made, and the geometric average of the values
was viewed as the best rational estimate of the slope factor
(EPA, 1986a) . The EPA's CRAVE workgroup has reviewed and
accepted this approach to slope factor estimation as a method to
include all relevant data (EPA, 1987) .
This averaging approach to slope factor estimation utilizing
multiple studies, species, strains and sexes has not generally
been recommended in earlier EPA guidelines (EPA, 1980; 1986b) .
However, more recently, EPA (1989) has stated: "Occasionally, in
situations where no single study is judged most appropriate, yet
several studies collectively support the estimate, the geometric
mean of estimates from all studies may be adopted as the slope.
This practice insures the inclusion of all relevant data" (EPA,
1989) . In the specific case of DDT, the averaging process as
applied to the best available studies may be the most reasonable
means of quantitatively characterizing the carcinogenicity of DDT
(Schoeny, 1991; Holder, 1991; Bayard, 1991) .
The Tier 1 Human Cancer Criteria for DDT are derived from
the slope factor of 3.4 x ID'' (mg/kg/d)-' baged Qn rodent
tumor induction in the six key studies.
RAD = Risk Level = _ 1 x IP'5 _
ql* • 3.4 x ID'1 (mg/kg/d)-1
= 2.94 x 10'5 mg/kg/d
Drinking Water Sources:
HCV = _ RAD x BW _
WC + [(FC x BAF.) + (FC x
2.94 x IP'5 mcr/ka/d x 70 kg
2 1/d + [(0.0036 x 376,400) + (0.0114 x 1,114,000)]
1.5 x 10"* ug/L
21
-------
Non-Drinking Water Sources:
HCV = _ RAD x BW
WCr + [(FCru x BAF^) + (FCru x
2.94 x IP'5 mo/kcr/d x 70 ka
0.01 1/d + [(0.0036 x 376,400) + (0.0114 x 1,114,000)]
- 1.5 x ID"4 ug/L
References:
Bayard, S. 1991.. Toxicologist/Statistician with the U.S. EPA
Office of Research and Development, Human Health Assessment
Group. Personal communication with R. Sills, Michigan Department
of Natural Resources.
Cabral, J. et al. 1982. Effects of long-term intake of DDT on
rats. Tumori 68:11-17.
Holder, J. 1991. Toxicologist with the U.S. EPA Office of
Research and Development, Human Health Assessment Group.
Personal communication with R. Sills, Michigan Department of
Natural Resources.
Rossi, L. et al. 1977. Long-term administration of DDT or
phenobarbital-Na in Wistar rats. Int. J. Cancer. 19:179-185.
Schoeny, R. 1991. U.S. EPA Environmental Criteria Assessment
Office, Chair of the Cancer Risk Assessment Verification Endeavor
(CRAVE) workgroup. Personal communication with R. Sills,
Michigan Department of Natural Resources.
Tarjan, R. and T. Kemeny. 1969. Multigeneration studies on DDT
in mice. Food Cosmet. Toxicol. 7:215-222.
Terracini, B. et al. 1973. The effects of long-term feeding of
DDT to BALB/c mice. Int. J. Cancer. 11:747-764.
Thorpe, E. and A'. Walker. 1973. The toxicology of dieldrin.
II. Comparative long-term oral toxicity studies in mice with
dieldrin, DDT, phenobarbital, beta-BHC and gamma-BHC. Food
Cosmet. Toxicol. 11:433-442.
Tomatis, L. and V. Turusov. 1975. Studies on the
carcinogenicity of DDT. Gann Monograph on Cancer Research.
17:219-241.
Turusov, V. et al. 1973. Tumors in CF-l mice exposed for six
consecutive generations to DDT. J. Natl. Cancer Inst. 51:983-
998.
22
-------
U.S. Environmental Protection Agency (EPA). 1980. 45 Federal
Register No. 231, pp. 79347-79356. Appendix C - Guidelines and
Methodology Used in the Preparation of the Consent Decree Water
Criteria Documents.
U.S. Environmental Protection Agency (EPA). I986a: The
Assessment of the Carcinogenicity of Dicofol (Kelthane), DDT,
DDE, and DDD (TDE). OHEA/ORD. EPA/600/6-86/001. PB 87-110904.
U.S. Environmental Protection Agency (EPA). 1986b. 51 Federal
Register No. 185, pp. 33992-34003. Guidelines for Carcinogen
Risk Assessment.
U.S. Environmental Protection Agency (EPA). 1987. Intergrated
Risk Information System (IRIS database). Chemical file for DDT
(59-29-3). Verification Date 6/24/87. Last Revised 5/1/91.
U.S. Environmental Protection Agency (EPA). 1989. Risk
Assessment Guidance for Superfund. Volume 1. Human Health
Evaluation Manual (Part A). Interim Final. OERR. EPA/540/1-
89/002.
23
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GREAT LAKES WATER QUALITY INITIATIVE
TIER 1 HUMAN HEALTH CRITERIA FOR
DIELDRIN
CAS NO. 60-57-1
Tier 1 HiTnu*'n ^oncancer Criterion
A review of the available literature indicates that the most
appropriate study for HNC derivation for dieldrin is a two year
study conducted by Walker et al. (1969). In this study, 25
Carworth Farm "E" rats of each sex were administered 0.1, 1.0 or
10.0 ppm dieldrin in their diet and 45 rats of each sex were used
as controls. At the end of two years, the females exposed to 1.0
and 10.0 ppm had increased liver weights and liver-to-body weight
ratios. Histopathological examination of these animals found
changes in perenchymal cells which included focal proliferation
and focal hyperplasia. A NOAEL of 0.1 ppm (estimated to be 0.005
mg/kg/day) was determined from the study. In support of this
value a systemic NOEL of 0.005 mg/kg/day was calculated for dogs
in the same study.
Studies examining the reproductive effects of dieldrin are
lacking (EPA, 1987) . A review of studies which examine the
developmental effects of dieldrin in mice (Chernoff et al., 1975;
Dix et al., 1977) and rats (Harr et al., 1970; Chernoff et al.,
1975) suggest that exposure levels which may result in adverse
developmental effects are higher than the NOAEL determined in the
Walker et al. (1969) study.
The quality of the Walker et al. (1969) study was deemed
sufficient to derive a Tier 1 HNC. This study was also used by
EPA (1987) to derive the oral RfD for dieldrin. The HNC was
derived from the NOAEL (0.005 mg/kg/day) using an uncertainty
factor of 100 to account for interspecies variability and
intraspecies differences.
•
ADE = NOAEL = 0.005 ma/ka/d = 5.0 x 10'5 mg/kg/d
UF 100
Where: Uncertainty Factor = 100, composed of:
lOx for interspecies variability
lOx for intraspecies differences
Drinking Water Sources:
HNV = ADE x BW x RSC
WCd + [(FCTL3 x BAFTu) + (FC™ x BAF™)]
= 5.0 x IP'5 ma/ka/d x 70 ka x 0.8
2 1/d + [(0.0036 x 72,610) + (0.0114 x 571,000)]
= 4.1 x ID"4 ug/L
24
-------
Non-Drinking Water Sources:
HNV = _ APE x BW X RSC
WCr + [ (FCru x BAFra) + (FC™ x
5.0 x IP'5 mcr/kcr/d x 70 ko x 0.8
0.01 1/d + [(0.0036 x 72,610) + (0.0114 x 571,000)]
= 4.1 x 10"* ug/L
References :
Chernoff, N., R.J. Kavlock, J.R. Kathrein, J.M. Dunn and J.K.
Haseman. 1975. Prenatal effects of dieldrin and photo-dieldrin
in mice and rats. Toxicol. Appl. Pharmacol. 31:302-308.
Dix, K.M., C.L. Van Der Paus and W. B. McCarthy. 1977. Toxicity
studies with dieldrin: teratological studies in mice dosed
orally with HEOD. Teratology 16:57-62.
Harr, J.R., R.R. Claeys, J.F. Bone and T.W. McCorcle. 1970.
Dieldrin toxicosis: Rat reproduction. Am. J. Vet. Res. 31:181-
189.
U.S. Environmental Protection Agency (EPA) . 1987. Integrated
Risk Information System (IRIS database) . Chemical file for
dieldrin (60-57-1). Verification Date 4/16/87. Last Revised
9/1/90.
Walker, A.I.T., D.E. Stevenson, J. Robinson, E. Thorpe and
M. Roberts. 1969. The toxicology and pharmacodynamics of
dieldrin (HEOD) : Two year oral exposures of rats and dogs.
Toxicol. Appl. Pharmacol. 15:345-373.
Tier 1 H"71"*11 Ctmcer Criterion
According to EPA (1987a) , there are inadequate data
available to ascertain whether dieldrin is a human carcinogen.
However, chronic- studies have shown that dieldrin induces the
formation of liver tumors in seven strains of mice when
administered orally. Additional support for dieldrin 's
carcinogenicity is provided by its structural similarity to other
compounds (i.e. heptachlor and chlordane) which have been found
to induce tumors in rodents. Dieldrin has also produced a
positive response in several mutagenicity studies. The weight -
of -evidence for dieldrin carcinogenicity is sufficient for B2
(probable human carcinogen) classification (EPA, 1987a) . The
data are sufficient to derive a Tier l HCC.
Six key studies (Davis, 1965 as reevaluated by Reuber and
cited in Epstein, 1975; Walker et al., 1972; Thorpe and Walker,
25
-------
1973; NCI, 1978; Tennekes et al., 1981; Meierhenry et al., 1983)
have reported liver tumor induction in mice exposed orally to
dieldrin. EPA (1987a; 1987b) calculated 13 different slope
factors using data from these studies. The calculated slope
factors were within an eight-fold range. EPA (1987a; 1987b)
calculated a single oral slope factor of 1.6 x 101 (mg/kg/day)"1
by taking the geometric mean of the 13 slope factors computed
from the key studies. This method of computing a slope factor is
used "in situations where no single study is judged most
appropriate, yet several studies collectively support the
estimate..." (EPA, 1989). According to EPA (1989), the advantage
of this method of determining the slope factor is that all
relevant data are used in the computation.
RAD = Risk Level = 1 x IP'5
ql* 1.6 x 10' (mg/kg/d)'1
= 6.25 x ID'7 mg/kg/d
Drinking Water Sources:
•
HCV - RAD x BW
WCd + [(FCnj x BAFro) + (PC™ x BAF^) ]
= 6.25 x IP'7 ma/kQ/d x 70 ka
2 1/d + [(0.0036 x 72,610) + (0.0114 x 571,000)]
= 6.5 x 10"6 ug/L
Non-Drinking Water Sources:
HCV = RAD X BW
WCr + [(FCru x BAF^) + (FCn,, x BAF^) ]
= 6.25 x 10'7 mg/kg/d x 70 kg
0.01 1/d + [(0.0036 x 72,610) + (0.0114 x 571,000)]
- 6.5 x ID"6 ug/L
References:
Davis, K.J. 1965. Pathology report on mice fed aldrin,
dieldrin, heptachlor or heptachlor epoxide for two years.
Internal FDA memorandum to Dr. A. J. Lehman. July 19. As cited
in: Epstein, 1975; EPA, 1987a.
Epstein, S.S., 1?75. The carcinogenicity of dieldrin. Part 1.
Sci. Total Environ. 4:1-52.
26
-------
Meierhenry, E.F., B.H. Reuber, M.E. Gershwin, L.S. Hsieh and
S.W.French. 1983. Dieldrin-induced mallory bodies in hepatic
tumors of mice of different strains. Hepatology. 3:90-95.
National Cancer Institute. 1978. Bioassays of aldrin and
dieldrin for possible carcinogenicity. DHEW Publication No.
(NIH) 78-822. National Cancer Institute Carcinogenesis Technical
Report Series, No. 22. NCI-CG-TR-22.
Tennekes, H.A., A.S. Wright, K.M. Dix and J.H. Koeman. 1981.
Effects of dieldrin, diet and bedding on enzyme function and
tumor incidence in livers of male CF-1 mice. Cancer Res.
41:3615-3620.
Thorpe, E. and A.I.T. Walker. 1973. The toxicology of
dieldrin(HEOD). Part II. Comparative long-term oral toxicology
studies in mice with dieldrin, DDT, phenobarbitone, beta-BHC and
gamma-BHC. Food Cosmet. Toxicol. 11:433-441.
U.S. Environmental Protection Agency (EPA). 1987a. Integrated
Risk Information System (IRIS database). Chemical file for
chlordane (57-74-9). Verification Date 3/5/87. Last Revised
1/1/91.
U.S. Environmental Protection Agency (EPA). 1987b.
Carcinogenicity Assessment of Aldrin and Dieldrin. Prepared by
Carcinogen Assessment Group, Office of Health and Environmental
Assessment, Washington, DC for Hazard Evaluation Divieion, Office
of Pesticide Programs, Office of Pesticides and Toxic Substances.
OHEA-C-205.
U.S. Environmental Protection Agency (EPA). 1989. Ri«k
Assessment Guidance for Superfund. Volume 1. Human Health
Evaluation Manual (Part A). Interim Final. OERR. EPA/540/1-
89/002.
Walker, A.I.T., E. Thorpe and D.E. Stevenson. 1972. The
toxicology of dieldrin (HEOD). I. Long-term oral toxicity
studies in mice. Food Cosmet. Toxicol. 11:415-432.
27
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GREAT LAKES WATER QUALITY INITIATIVE
TIER 1 HUMAN HEALTH CRITERIA FOR
2,4-DIMETHYLPHENOL
CAS NO. 105-67-9
er l H"*1"*" oncancer Criterion
A review of the available literature indicates that HNV
derivation for 2 , 4 - dimethylphenol (2,4-DMP) is most appropriately
based on the subchronic oral mouse study conducted by EPA (1989) .
Groups consisting of 30 male and 30 female albino mice were
administered 2,4-DMP by gavage at dose levels of 0, 5, 50 or 250
mg/kg/day for 90 days. At day 30, an interim sacrifice was
performed on at least 8 males and 9 females from each group.
Effects examined included mortality, clinical signs, body
weights, food consumption, ophthalmology, hematology, clinical
chemistry, organ weights, and gross histopathology.
Toxicologically relevant clinical signs observed only after week
6 at 250 mg/kg/day in both sexes included squinting, lethargy,
prostration, and- ataxia, with onset shortly after dosing.
Statistically significant lower mean corpuscular volume and mean
corpuscular hemoglobin concentrations were observed in female
mice at 250 mg/kg/day during the final but not during the interim
sacrifice. At interim sacrifice, the blood urea nitrogen (BUN)
levels for females at 50 and 250 mg/kg/day were significantly
lower than the vehicle controls, while at the final sacrifice,
the BUN levels for females at 50 mg/kg/day were significantly
higher than the vehicle control group. For only the low- dose (5
mg/kg/day) males' at the interim sacrifice, cholesterol levels
were significantly higher than the vehicle control group.
Increased adrenal weights were observed in low- dose (5 mg/kg/day)
but not mid- to high- dose females when compared to vehicle
control animals. Since the reported changes in BUN, serum
cholesterol and adrenal weights were not dose- or time -dependent,
they may be interpreted to be spurious findings. The NOAEL and
LOAEL for this study were 50 and 250 mg/kg/day, respectively,
based on clinical signs and hematological changes.
The database is judged to be sufficient for Tier 1 HNC
derivation because the key study (EPA, 1989) provides a
subchronic NOAEL. However, there is a paucity of supplemental
and supportive data. No useful chronic, reproductive or
developmental studies are available. The overall findings from
the 90 -day study (EPA, 1989) compare favorably with the results
of a 14 -day mice gavage study (EPA, 1987; as cited in EPA, 1989;
EPA, 1990) conducted at the same laboratory. In the 14 -day
study, the only toxicological signs observed in males and females
administered 250 mg/kg/day were lethargy, prostration, and
ataxia. This is the same dose at which critical effects were
found in the 90-day study (EPA, 1989) .
The HNV is derived from the NOAEL dose of 50 mg/kg/day from
the 90-day gavage mouse study by EPA (1989) with an uncertainty
28
-------
factor of 3000. This approach is consistent with the derivation
of the oral RfD for 2,4-DMP by EPA (1990).
ADE = NOAEL = 50 mg/ko/d = 1.67 x 10'2 mg/kg/d
UF 3000
Where: Uncertainty Factor = 3000, composed of:
lOx for interspecies variability
lOx for intraspecies differences
lOx for subchronic exposure duration
3x for substantial gaps in the database
Drinking Water Sources:
HNV = _ ADE x BW x RSC _
WCd + [
- 1.67 x IP'2 ma/kq/d x 70 ko x 0.8
2 1/d + '[(0.0036 x 5) + (0.0114 x 7)]
= 4.5 x 102 ug/L
Non-Drinking Water Sources:
HNV = _ ADE x BW x RSC _
WCr + [ (FCnj x BAFro) + (FC^ x
= 1.67'x IP'2 ma/kq/d x 70 kg x 0.8
0.01 1/d + [(0.0036 x 5) + (0.0114 x 7)]
- 8.7 x 103 ug/L
References:
U.S. Environmental Protection Agency (EPA). 1990. Integrated
Risk Information System (IRIS database). Chemical file for 2,4-
dimethylphenol (105-67-9). Verification Date 2/21/90. Last
Reviewed 2/21/90.
U.S. Environmental Protection Agency (EPA). 1989. Ninety-Day
Gavage Study in Albino Mice Using 2,4-Dimethylphenol. Study No.
410-2831, prepared by Dynamac Corporation, Rockville, MD, for the
Office of Solid Waste and Emergency Response, Washington, DC.
U.S. Environmental Protection Agency (EPA). 1987. Fourteen-Day
Gavage Study in Albino Mice Using 2,4-Dimethylphenol. Study No.
410-2830, prepared by Dynamac Corporation, Rockville, MD, for the
Office of Solid Waste and Emergency Response, Washington, DC. As
cited in EPA (1989, 1990).
29
-------
U.S. Environmental Protection Agency (EPA). 1980. Ambient Water
Quality Criteria for 2,4-Dimethylphenol. Office of Water
Regulations and Standards, Criteria and Standards Division,
Washington, DC. EPA 440/5-80-044. PB81- 117558.
Criterion
2,4-Dimethylphenol is not considered carcinogenic.
30
-------
GREAT LAKES WATER QUALITY INITIATIVE
TIER 1 HUMAN HEALTH CRITERIA FOR
2,4-DINITROPHENOL
CAS NO. 51-28-5
r 1 Hi"^?*1 Nonci*T|cer Criterion
A review of the available literature on the toxic effects
and therapeutic use of 2,4-dinitrophenol (2,4-DNP) indicates that
the HNC derivation is most appropriately based upon the human
dose-response following exposure to 2,4-DNP as reviewed by Horner
(1942) .
Numerous studies on 2,4-DNP and its toxic effects on humans
are available (Horner, 1942; SRC, 1981) . Commonly -reported toxic
effects included gastrointestinal disturbances (nausea, vomiting,
loss of appetite), cutaneous rashes, neuritis, agranulocytosis of
the bone marrow, and jaundice. Liver and kidney and
cardiovascular damage was rarely reported. Evidence of
cardiovascular effects was limited to abnormal electrocardiograms
indicating functional abnormalities of the heart, although
fragmentation of the heart muscle was reported in cases of fatal
poisoning. Nine cases of mortality resulting from 2,4-DNP
poisoning were cited. Death usually occurred within 24 hours
after the onset of such toxic manifestations as dizziness,
fatigue, dyspnea, high temperature, intense thirst, and excessive
perspiration .
In the study by Horner (1942) , bilateral cataract formation
was frequently observed in patients receiving 2,4-DNP as a
weight -loss agent. The study reported that cataracts developed
in more than 164' persons after the use of dinitrophenol , an
estimated incidence of 0.86 percent. The study did not include a
control group, however the researcher noted that this type of
cataract is not expected to occur in some of the age groups which
exhibited cataracts in the study. Formation of cataracts
occurred either during dosing or within several months to a year
after the final dose was taken. Cataracts were observed in
patients receiving as little as 2 mg/kg bw/day which was the
lower range of the recommended therapeutic dose for obesity.
This LOAEL determined from the Horner (1942) study was deemed
sufficient for the derivation of a Tier 1 HNC.
In a 6 -month feeding study, male rats (from the Breeding and
Laboratory Institute, Brooklyn, NY) were administered 2,4-DNP at
dietary levels of 0, 100, 200, 500 and 1000 ppm for 178-179 days
(Spencer et al., 1948) . There were 14, 12, 12, 9 and 14 rats per
dietary level, respectively. An additional 10 rats were fed 2000
ppm but after 24 days this group experienced 40% mortality and
the remaining animals at 2000 ppm were sacrificed and examined at
this time. These animals were emaciated and had empty
gastrointestinal tracts, enlarged spleens with hemosiderosis,
testicular atrophy, and increased levels of blood urea nitrogen.
Rats fed 1000 ppm 2,4-DNP suffered a reduction in body weight
31
-------
gain of 10-15%, a slight depletion of body fat, a very slight
increase in the average weight of the kidneys, and a very slight
decrease in the weight of the heart. Blood urea nitrogen levels
were elevated in 2/14 animals at 1000 ppm. Reduced growth
occurred at 500 ppm and a significant increase (between 91% and
92% above controls) in kidney weights occurred at all dietary
concentrations. The authors concluded that the male rats
maintained for six months on diets containing 200 ppm (and
presumably 100 ppm) showed no appreciable ill effects. However,
because there was a statistically significant increase in kidney
weights at all dietary concentrations, the dose of 100 ppm may be
considered the LOAEL for this study. Using a food consumption
value of 0.08 kg/kg bw (EPA, 1988), the LOAEL for the Spencer et
al. (1948) study was 8 mg/kg bw/day. This is very close to the
LOAEL of 2.0 mg/kg bw/day which was calculated using the human
data from Horner (1942) . EPA (1980) derived an Acceptable Daily
Intake (ADI) from an estimated NOAEL of 5.4 mg/kg/day (100 ppm
group) from the study by Spencer et al. (1948) .
In a teratology study with 2,4-DNP, Gibson (1973) reported
that neither intraperitoneal (7.7 and 13.6 mg/kg/day) nor oral
(25.5 and 38.2 mg/kg/day) doses of 2,4-DNP administered to
pregnant Swiss -Webster mice during early organogenesis (days 10-
12 of gestation) produced morphological defects. However, the
higher intraperitoneal dose was embryotoxic and the higher
intraperitoneal and oral doses produced overt signs of toxicity
(hyperexcitability and hyperthermia) in the dams.
The HNV is derived from the LOAEL (2.0 mg/kg bw/day)
determined from the human data summarized by Horner (1942) using
an uncertainty factor of 1000. This approach is consistent with
the derivation of the oral RfD for 2,4-DNP by EPA (1986) .
ADE = NOAEL = 2 mcr/kcr/d = 2.0 x 10'3 mg/kg/d
UF 1000
Where: Uncertainty Factor = 1000, composed of:
lOx for interspecies variability
lOx for intraspecies differences
lOx for subchronic exposure duration
Drinking Water Sources:
HNV = _ ADE X BW X RSC _
WCd + [(FCnj x BAF-ru) + (FC^ x
= 2.0 x IP'3 ma/ka/d x 70 ka x 0.8
2 1/d + .[(0.0036 x 2) + (0.0114 x 2)]
- 55 ug/L
Non-Drinking Water Sources:
32
-------
HNV = _ APE x BW x RSC
WCr + [(Peru x BAF-ru) + (FC^ x
= 2.0 x IP'3 ma/ka/d x 70 ka x 0 . 8 _
0.01 1/d + [(0.0036 x 2) + (0.0114 x 2)]
= 2.8 x 103 ug/L
References :
Gibson, J.E. 1973. Teratology studies in mice with 2-
secbutyl-4, 6 - dinitrophenol (dinoseb) . Food Cosmet.
Toxicol.ll:31-43-.
Horner, W.D. 1942. Dinitrophenol and its relation to formation
of cataracts. Arch. Ophthal. 27:1097-1121.
Spencer, H.C., V.K. Rowe, E.M. Adams and D.D. Irish. 1948.
Toxicological studies on laboratory animals of certain alkyl
dinitrophenols used in agriculture. J. Indus. Hyg. Toxicol.
30:10-25.
•
Syracuse Research Corporation (SRC) , Center for Chemical Hazard
Assessment. 1981. Information Profiles on Potential
Occupational Hazards: Nitrophenols . Prepared for National
Institute for Occupational Safety and Health (NIOSH) , Rockville,
MD. PB89-215842/XAD. PHS-NIOSH-210-79-0030 .
U.S. Environmental Protection Agency (EPA). 1988.
Recommendations For And Documentation Of Biological Values For
Use In Risk Assessment. PB88- 179874.
U.S. Environmental Protection Agency (EPA). 1986. Integrated
Risk Information System (IRIS database). Chemical file for 2,4-
dinitrophenol (51-28-5) . Verification Date 2/5/86. Last
Reviewed 2/5/86.
U.S. Environmental Protection Agency (EPA) . 1980. Ambient Water
Quality Criteria Document for Nitrophenols. Prepared by the
Office of Health' and Environmental Assessment, Environmental
Criteria and Assessment Office, Cincinnati, OH for the Office of
Water Regulations and Standards, Criteria and Standards Division,
Washington, DC. EPA 440/5-80-063.
Tier 1 Human Cancer Criterion
2, 4 -Dinitrophenol is not considered carcinogenic.
33
-------
GREAT LAKES WATER QUALITY INITIATIVE
TIER 1 HUMAN HEALTH CRITERIA FOR
CAS NO. 118-74-1
Tier i HIHIIJITI Mpncancer Criteria
A review of the available information on hexachlorobenzene
(HCB) toxicity, including reviews by EPA (1980; 1985a; 1985b;
1988) , indicates that the database is sufficient for Tier 1 HNC
derivation. The best available data consist of laboratory animal
studies .
The principle human data on HCB toxicity consist of
widespread toxic effects among several thousand Turkish citizens
exposed to HCB via consumption of fungicide -treated grain during
1955-1959. The resulting effects included porphyria cutanea
tarda (PCT) , neurotoxicity, liver damage, and increased infant
mortality. The exposure has been estimated at 50-200 mg/day over
an extended period, without further description of the dosage
estimation method (Cam and Nigogosyan, 1963) . The human data
cannot be used for quantitative risk assessment because accurate
exposure data are not available (EPA, 1988) .
The available literature indicates that HCB is a potent
developmental toxicant in several animal species. Kitchin et al.
(1982) exposed rats to 0, 60, 80, 100, 120 and 140 ppm HCB in
feed (doses ranged from 0 to 10 mg/kg/day) . They reported a
dose -dependent increase in mortality of pups in the Fla and Flb
litters. Grant et al. (1977) conducted a 4 -generation
reproduction study with rats at food HCB levels in the diet of 0,
10, 20, 40, 80, 160, 320 and 640 ppm. They concluded that 20 ppm
(about 1.5 mg/kg/day) was a NOAEL, while 40 ppm (about 3
mg/kg/day) resulted in increased liver weights in weanlings.
Rush et al. (1983) exposed mink to 0, 1 or 5 ppm in feed
(about 0.16 or 0.78 mg/kg/day), resulting in profound effects on
kit survivability to weaning at the high dose. Mortality was 8.2
percent, 4.1 percent and 77.4 percent among controls, low dose,
and high dose groups, respectively. Bleavins et al. (1984a,
1984b) also reported that mink, as well as ferrets, are highly
sensitive to the developmental effects of HCB. Mink were found
to be more sensitive than ferrets, while both appeared more
sensitive than rats according to published data. The most
profound effects reported were decreased mink birth weights at
adult dietary levels as low as 1 ppm and a dose -related increase
in kit mortality, at three weeks of age among both mink and
ferrets at levels as low as 1 ppm (about 0.14 and 0.11 mg/kg/day
for mink and ferrets, respectively) . Additionally, effects were
seen on the levels of hypothalamic dopamine of mink kits and on
hypothalamic serotonin in adult mink. These changes were
statistically significant at levels as low as 1 ppm in feed. A
NOAEL was not reported.
34
-------
Arnold et al. (1985) exposed male and female rats to dietary
HCB levels of 0, 0.32, 1.6, 8.0 or 40 ppm for 90 days prior to
mating and until 21 days after parturition (at weaning). The
offspring were exposed in utero, from maternal nursing, and from
their diets for the remainder of their lifetime. The total study
period was 130 weeks. A NOAEL was reported at 1.6 ppm (about
0.08 mg/kg/day). At 8 ppm (0.29 mg/kg/day) the parental (Fo)
males demonstrated increased heart and liver weights and the Fl
generation had an increased incidence of hepatic centrilobular
basophilic chromogenesis. The 40 ppm Fl groups showed increases
in pup mortality, hepatic centrilobular basophilic chromogenesis,
and severe chronic nephritis (males only).
The effects of HCB on adult animals has been further
demonstrated in many other studies, a few of which report NOAELs.
Kuiper-Goodman et al. (1977) exposed rats via the diet to 0, 0.5,
2, 8 and 32 mg/kg bw/day for up to 15 weeks. A NOAEL was
reported at 0.5 mg/kg/day, while at the higher dose levels,
increased tissue porphyrin, increased organ weights and increased
severity of centrilobular liver lesions were noted. Grant et al.
(1974) exposed rats to HCB at dietary levels of 10, 20, 40, 80
and 160 ppm for 9-10 months. Porphyria was induced at levels as
low as 20 ppm (about 1 mg/kg/day).
The data selected for HNC determination are from the Arnold
et al. (1985) study. This study involved the exposure of adult
male and female Sprague-Dawley rats and subsequent exposure of
the offspring in utero, via lactation, and via the diet. Cross-
fostering studies have demonstrated that the neonate is
particularly sensitive to the toxic effects of HCB. The transfer
of HCB to neonates via the milk of exposed adults has also been
shown to be significant (Bailey et al. 1980; Bleavins et al.
1982). The Arnold et al. (1985) study demonstrated NOAELs of
0.32 and 1.6 ppm. in feed (estimated to be 0.016 and 0.08
mg/kg/day). Therefore, the NOAEL of 0.08 mg/kg/day, with an
uncertainty factor of 100 (lOx for interspecies variation and lOx
for intraspecies differences) is used for HNC derivation.
Consideration was also given to the mink and ferret data (Rush et
al., 1983; Bleavins et al., 1984a, 1984b) which demonstrate that
these species are highly sensitive to the developmental toxic
effects of HCB. Adverse effects on the development of mink and
ferrets have been reported at doses only slightly higher than the
rat NOAEL of 0.06 mg/kg/day. However, the rat NOAEL is utilized
preferentially because the Sprague-Dawley rat, unlike the mink or
ferret, has been extensively studied as an animal model for
toxicity testing, and the high quality of the Arnold et al.
(1985) study. The selection of this key study is consistent with
EPA'S RfD for HCB (1988).
ADE = NOAEL = 0.08 ma/ko/d = 8 x W4 mg/kg/day
UF 100
Where: Uncertainty Factor = 100, composed of:
35
-------
lOx for interspecies variability
lOx for intraspecies differences
Drinking Water Sources:
HNV = _ APE x BW x RSC
WCd + [ (FCTL3 x BAFTLg) + (FCru x
8 x 10"4 m/k/d x 70 k x 0.8
2 1/d + [(0.0036 x 43,690) + (0.0114 x 71,080)]
- 4.6 x 10:2 ug/L
Non-Drinking Water Sources:
HNV «= _ APE x BW x RSC _
WCr + [(FC^ x BAF^) + (FC™ X BAF^) ]
= _ 8 x 10 "* mcr/kg/d x 70 kg x 0.8 _
0.01 1/d. + [(0.0036 x 43,690) + (0.0114 x 71,080)]
= 4.6 x 10'2 ug/L
References :
Arnold, D.L. et al. 1985. Long-term toxicity of
hexachlorobenzene in the rat and the effect of dietary vitamin A.
Fd. Chem. Toxic. 23 (9) : 779 -793.
Bailey, J. , V. Knauf, W. Mueller and W. Hobson. 1980. Transfer
of hexachlorobenzene and polychlorinated biphenyls to nursing
infant rhesus monkeys: Enhanced toxicity. Environ. Res. 21(1):
190-196.
Bleavins, M.R. , W.J. Breslin, R.J. Aulerich and R.K. Ringer.
1982. Excretion and placental and mammary transfer of
hexachlorobenzene in the European ferret (Mustela putorius furo) .
J. Toxicol. Environ. Health. 10:929-940.
Bleavins, M. , R. Aulerich and R. Ringer. 1984a. Effects of
chronic dietary hexachlorobenzene exposure on the reproductive
performance and survivability of mink and European ferrets.
Arch. Environ. Contain. Toxicol. 13:357-365.
Bleavins, M. et al. 1984b. Effects of dietary hexachlorobenzene
exposure on regional brain biogenic amine concentrations in mink
and European ferrets. Toxicol. Environ. Hlth. 14:363-377.
Cam, C. and G. Nigogosyan. 1963. Acquired toxic porphyria
cutaneatarda due to hexachlorobenzene. Report of 348 cases
caused by this fungicide. J. Am. Med. Assoc. 183:88-91.
36
-------
Grant, D. et al. 1974. Effects of hexachlorobenzene on liver
porphyrin levels and microsomal enzymes in the rat. Environ.
Physiol. Biochem. 4:159-165.
Grant, D., W. Phillips and G. Hatina. 1977. Effect of
hexachlorobenzene on reproduction in the rat. Arch. Environ.
Contain. Toxicol. 5 (2) :207-216.
Kitchin, K. et al. 1982. Offspring mortality and maternal lung
pathology in female rats fed hexachlorobenzene. Toxicol. 23:33-
39.
Kuiper-Goodman, T. et al. 1977. Subacute toxicity of
hexachlorobenzene in the rat. Toxicol. and Appl. Pharmacol.
40:529-549.
Rush, G. et al. 1983. Perinatal hexachlorobenzene toxicity in
the mink. Environ. Res. 31:116-124.
U.S. Environmental Protection Agency (EPA). 1980. Ambient Water
Quality Criteria for Chlorinated Benzenes. EPA 440/5-80-028.
•
U.S. Environmental Protection Agency (EPA). 1985a. Drinking
Water Criteria Document for Hexachlorobenzene (Final Draft). EPA
- 600/X-84-179-1. PB-86-117777.
U.S. Environmental Protection Agency (EPA). 1985b. Health
Assessment Document for Chlorinated Benzenes. EPA/600/8-84/015F.
U.S. Environmental Protection Agency (EPA). 1988. Integrated
Risk Information- System (IRIS database). Chemical file for
hexachlorobenzene (118-74-1). Verification Date 5/26/88. Last
Revised 4/1/91.
A review of the available literature indicates that there
are inadequate human data, but sufficient animal carcinogenicity
data to support a B2 weight-of-evidence classification (EPA,
1989). The animal bioassays, which have been comprehensively
reviewed and summarized by EPA (1980; 1985a; 1985b; 1989),
indicate that HCB induces tumors of the liver predominantly, with
neoplasm induction of the thyroid and kidney also reported. The
data are judged sufficient for Tier l HCC derivation.
EPA (1991) derived an oral slope factor of 1.6 (mg/kg/day) ~l
from a chronic rat bioassay demonstrating hepatocellular
carcinoma induction (Erturk et al., 1986). This slope factor is
among the highest of those derived for HCB from 14 different
datasets, which fell within a range of 8.3 E-2 to 1.7 E+0 (EPA,
1989). This dataset was also selected for slope factor
37
-------
estimation because the study was well-conducted and the tumors
were malignancies of the primary target organ (liver cancers) .
In the key study, Erturk et al. (1986; abstracts previously
published as Lambrecht et al., 1983a; 1983b) exposed groups of 94
Sprague-Dawley rats/sex/dose to HCB via feed at 0, 75 or 150 ppm
in the diet for up to two years. Treated animals of both sexes
surviving past 12 months showed significant increases in liver
and renal tumors. Females were far more susceptible to hepato-
carcinogenicity while males were generally more sensitive to
renal carcinogenicity. The slope factor of 1.6 per (mg/kg) /day
is derived from the induction of hepatocellular carcinomas in
female rats. This is consistent with EPA (1989).
RAD = Risk Level «= 1 x IP'5
ql* 1.6 (mg/kg/d)'1
- 6.25 x 1CT6 mg/kg/d
Drinking Water Sources:
HCV = _ RAD x BW _
WCd + [(FCnj x BAFra) + (FC^ x
6.25 x 1Q-6 ma/ka/d x 70 ka
2 1/d + [(0.0036 x 43,690) + (0.0114 x 71,080)]
= 4.5 x ID"4 ug/L
Non-Drinking Water Sources:
HCV = _ RAD x BW __
WCr + [(FCnj x BAFTLS) + (FC^ x
6.25 x IP"6 ma/ko/d x 70 ka
0.01 1/d + [(0.0036 x 43,690) + (0.0114 x 71,080)]
= 4.5 x 10r* ug/L
References :
Erturk, E. et al. 1986. Oncogenicity of hexachlorobenzene. In:
Hexachlorobenzene : Proc. Int. Symp., C.R. Morris and J.R.P.
Cabral, Eds. IARC Scientific Publ. No. 77, Oxford University
Press, Oxford, pp. 417-423.
Lambrecht, R., et al. 1983a. Renal tumors in rats chronically
exposed to hexachlorobenzene (HCB) . Proceedings of the American
Association for Cancer Research 24:59.
38
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Lambrecht, R., et al. 1983b. Hepatocarcinogenicity of
chronically administered hexachlorobenzene in rats. Federation
Proceedings. 42(4):786.
U.S. Environmental Protection Agency (EPA). 1980. Ambient Water
Quality Criteria for Chlorinated Benzenes. EPA 440/5-80-028.
U.S. Environmental Protection Agency (EPA). 1985a. Drinking
Water Criteria Document for Hexachlorobenzene (Final Draft).
EPA-600/X-84-179-1. NTIS: PB 86-117777.
U.S. Environmental Protection Agency (EPA) . I985b. Health
Assessment Document for Chlorinated Benzenes. EPA/600/8-84/015F.
U.S. Environmental Protection Agency (EPA). 1989. Integrated
Risk Information System (IRIS database). Chemical file for
hexachlorobenzene (118-74-1). Verification Date 3/1/89. Last
Revised 3/1/91.
39
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GREAT LAKES WATER QUALITY INITIATIVE
TIER 1 HUMAN HEALTH CRITERIA FOR
CAS NO. 67-72-1
Noncancer Criteria.
A review of the available literature indicates that the most
appropriate basis for HNV derivation for hexachloroethane (HCE)
is the NOAEL from a 16 -week dietary study in rats (Gorzinski et
al., 1985; Gorzinski et al.f 1980, as cited in EPA, 1991). In
this study male and female CDF Fischer 344 rats (10/sex/group)
were administered a diet containing HCE at target levels of 0, 3,
30 and 100 mg/kg/day for 16 weeks. EPA (1991) reported that
actual dose levels were analyzed to be approximately 0, 1.3, 20
and 82 mg/kg/day. From analysis of eating patterns and
measurement of the time -related loss of HCE from the diets, a
conservative estimate of exposure was determined by the
investigators as 0, 1, 15 and 62 mg/kg/day (Gorzinski et al.,
1985) . The results indicate that male rats were slightly more
sensitive than female rats to the nephrotoxic properties of HCE.
Renal toxicity observed at 15 and 62 mg/kg/day in male rats
included pale and mottled kidneys; significant increase* in
absolute and relative kidney weights; slight to moderate renal
tubular atrophy and degeneration with or without peritubular
fibrosis; a slight to moderate increase in renal tubular
cytoplasmic clumping and droplet formation; and scattered or
isolated renal tubules with slight hypertrophy and/or dilation of
the proximal convoluted tubules. Liver weights were increased in
male rats given 62 mg/kg/day. The liver exhibited a Blight
swelling of the hepatocytes in males given 15 or 62 mg/kg/day.
Evidence of renal toxicity in female rats consisted of very
slight renal tubular atrophy and degeneration observed
histopathologically at the highest dose level. Female rats given
62 mg/kg/day also had an increase in relative liver weight ratios
unaccompanied by microscopic alterations. Based on this study, a
NOAEL of 1 mg/kg/day was derived for liver and kidney toxicity in
male rats. While EPA (1991) indicates a NOAEL of 1 . 3 mg/Kg/day
based on the analyzed low dose, the estimated NOAEL of 1.0
mg/kg/day (Gorzinski et al., 1985; EPA, 1987) is used in the HNV
derivation.
In a chronic (78 -week) gavage study with rats and mice, the
National Cancer Institute (NCI, 1978) administered HCE in a
cyclic manner to 50 male and 50 female Osborne- Mendel rats and
continuously to 50 male and 50 female B6C3F1 mice. The rats
received HCE in corn oil at doses of 250 and 500 mg/kg/day, 5
days per week for a period of 22 consecutive weeks, followed by a
1-week, treatment -free interval. Thereafter, until the end of
the 78 weeks, the rats were intubated for 4 consecutive weeks
followed by 1 treatment -free week, in a cyclical pattern, for a
total of 66 weeks of HCE treatment. The time -weighted -average
40
-------
doses for the rats for the 78-week period were 212 and 423
mg/kg/day. The mice were intubated orally with HCE in corn oil
at initial levels of 500 and 1000 mg/kg/day for 8 weeks with
these doses increased to 600 and 1200 mg/kg/day, respectively,
for the remaining 70 experimental weeks. A time-weighted-average
dose of 590 and 1179 mg/kg/day for the low and high doses,
respectively, was reported. The dosing regimes were followed by
an observation period of 33 or 34 weeks for rats and 12 or 13
weeks for mice. Renal tubular nephropathy was observed during
histopathological examination at the termination of the study in
all groups of treated animals. In rats, significant pathology
and mortality at both dose levels in the males precluded the
development of a NOAEL or LOAEL for HCE. For the mice, due to
the occurrence of hepatocellular carcinoma and non-neoplastic
toxic nephropathy in both sexes at both dose levels, neither a
NOAEL nor a LOAEL could be determined.
Because of the inconclusive nature of results from the NCI
(1978) study, additional toxicological and carcinogenesis studies
were conducted by administering HCE in corn oil by gavage to
groups of male and female F344/N rats (50/sex/group) 5 days per
week for 2 years (NTP, 1989). The male rats received doses of 0,
10 or 20 mg/kg/day while the females received doses of 0, 80 or
160 mg/kg/day. The foremost toxic effect was kidney toxicity,
demonstrated by increased incidence of mineralization and
hyperplasia of the pelvic transitional epithelium in dosed male
rats, increased severity of renal tubule hyperplasia in high
dosed male rats, and increased incidence and severity of renal
tubule hyperplasia in female rats. The LOAEL was 10 mg/kg bw/day
for male rats. In this study, it was hypothesized that the
increased sensitivity of male rats to the renal toxicity of HCE
was a result of the accumulation of a2u-globulin in hyaline
droplets synthesized by the liver and secreted into the blood
(EPA, 1991). It is then apparently filtered through the
glomeruli and partially reabsorbed through the proximal tubules.
In the presence of HCE, as well as several nonpolar hydrocarbons
such as decalin and gasoline, a^-globulin accumulates in hyaline
droplets in the renal tubular cells. a2u-Globulin is an excretory
protein in male but not female rats. This may explain the male's
greater sensitivity to kidney damage from HCE.
In a 13-week rat study, also by NTP (1989), groups of 10
F344/N rats of each sex were administered 0, 47, 94, 188, 375 or
750 mg/kg HCE in corn oil by gavage, 5 days/week for 13 weeks.
Five/10 male rats and 2/10 female rats at 750 mg/kg/day died
before the end of the study. The final mean body weight of male
rats that received 750 mg/kg/day was 19% lower than that of
vehicle controls. Compound-related clinical signs for both sexes
included hyperactivity at doses of a 94 mg/kg/day and convulsions
at a 375 mg/kg/day. The relative weights of liver, heart and
kidney were increased for exposed males and females. Kidney
lesions were seen in all dosed male groups, and the severity
increased with dose. Papillary necrosis and tubular cell
41
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necrosis and degeneration in the kidney and hemorrhagic necrosis
in the urinary bladder were observed in the five male rats at 750
mg/kg/day which died before the end of the study. At all lower
doses in males, hyaline droplets, tubular regeneration, and
granular casts were present in the kidney. No chemical -related
kidney lesions were observed in females. Foci of hepatocellular
necrosis were observed in several male and female rats at a 188
mg/kg/day.
Weeks et al. (1979) studied the effects of repeated exposure
to HCE vapor in 25 male and 25 female rats, 4 male dogs, 10 male
guinea pigs, 20 male or female quail and 22 pregnant rats per
exposure group. • The animals were exposed for 6 hours/day, 5
days/week for 6 weeks and doses were analyzed at 0, 15, 48 or 260
ppm of the HCE vapor (equivalent to 0, 145, 465 or 2515 mg/m3;
EPA, 1991) . Toxic effects at the highest concentrations included
tremors and other neurotoxic signs. No effects were observed at
s 465 mg/m3.
Weeks et al. (1979) performed an oral study, in which HCE
doses of 100, 320 and 1000 mg/kg/day were administered by gavage
to rabbits for 12 days. The two highest doses resulted in liver
degeneration and* necrosis, toxic tubular nephrosis of the
convoluted tubules of the corticomedullary region of the kidney,
minimal tubular nephrocalcinosis, and decreased body weights.
The NOAEL for this study was 100 mg/kg/day based on the effects
of HCE on the kidneys of male rabbits.
The database is judged to be sufficient for Tier 1 HNC
derivation. The key study (Gorzinski et al., 1985) provides a
subchronic NOAEL which is supported and supplemented by chronic
toxicity data (EPA 1989; EPA, 1991; NCI, 1978; NTP, 1989; Weeks
et al., 1979) . The HNC is based on the subchronic rat NOAEL of 1
mg/kg/day, with a total uncertainty factor of 1000. The LOAEL of
15 mg/kg/day resulted in male rat renal toxicity. It may be
argued that the high sensitivity of this endpoint is peculiar to
male rats, secondary to hyaline droplet formation and a2u-globulin
accumulation. However, liver affects also occurred at a LOEL of
15 mg/kg/day. The use of the NOAEL of 1 mg/kg/day for risk
assessment is consistent with the oral RfD development by EPA
(1987) and the Lifetime Health Advisory (EPA, 1991) .
ADE = NOAEL = 1.00 ma/ka/d = 1.0 x 10'3 mg/kg/day
UF 1000
Where: Uncertainty Factor = 1,000, composed of:
lOx for interspecies variability
lOx for intraspecies differences
lOx for subchronic exposure duration
Drinking Water Sources:
= ADE x BW x RSC
WCd + [(FC^ x BAF-TLS) + (PC™ x
42
-------
= 1.0 x IP'3 mo/ka/d x 70 kg x 0.8
2 1/d + [(0.0036 x 371) + (0.0114 x 532)]
= 6.0 ug/L
Non-Drinking Water Sources:
HNV «B APE x BW x RSC
WCr + [ (FCTL3 x BAF-iu) + (PC™ X BAF^) ]
= 1.0 x IP'3 ma/ka/d x 70 ka x 0.8
0.1 1/d * [(0.0036 x 371) + (0.0114 x 532)]
= 7.6 ug/L
References:
Gorzinski, S.J., R.J. Nolan, S.B. McCollister, D.C. Morden, E.A.
Hermann, D.A. Dittenbar, R.V. Kainis, J.E. Battjes and R.J.
Kociba. 1980. Hexachloroethane: Results of a 16-Week Toxicity
Study in the Diet of CDF Fischer 344 Rats. Toxicology Research
Laboratory, Dow Chemical U.S.A., Midland, MI. As cited in EPA
(1991).
Gorzinski, S.J., R.J. Nolan, S.B. McCollister, R.J. Kociba and
J.L. Mattsson. 1985. Subchronic oral toxicity, tissue
distribution and clearance of hexachloroethane in the rat. Drug
and Chem. Toxicol. 8 (3):155-169.
National Cancer Institute (NCI). 1978. Bioassay of
Hexachloroethane for Possible Carcinogenicity. NCI
Carcinogenesis Technical Report Series No. 68, NCI-CG-TR-68, DHEW
Publication No. (NIH) 78-1318.
National Toxicology Program (NTP). 1989. Toxicology and
Carcinogenesis Studies of Hexachloroethane (CAS No. 67-72-1) in
F344/N Rats (Gavage Studies). NTP Technical Report. NTP-TR-361,
NIH/PUB-89-2816, Order No. PB90-170895, 117 pp.
U.S. Environmental Protection Agency (EPA). 1991.
Hexachloroethane. Health Advisory. Office of Drinking Water,
Washington, DC. PB91-159657/XAD.
U.S. Environmental Protection Agency (EPA). 1989. Health and
Environmental Effects Document for Hexachloroethane.
Environmental Criteria and Assessment Office, Cincinnati, OH.
EPA/600/8-88/043,. PB88-178736/GAR. ECAO-CIN-G041.
U.S. Environmental Protection Agency (EPA). 1987. Integrated
Risk Information System (IRIS database). Chemical file for
43
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hexachloroe thane (67-72-1). Verification Date 4/16/87. Last
Reviewed 4/16/91.
Weeks, M.H., R.A. Angerhofer, R. Bishop, J. Thomas ino and C.R.
Pope. 1979. The toxicity of hexachloroethane in laboratory
animals. Amer. Ind. Hyg. Assoc. J. 40 (3) :187-199.
Criterion
A review of the available literature for HCE car cinogeni city
reveals a lack of adequate epidemiological data and two chronic
oral rodent bioassays (NCI, 1978; NTP, 1989). EPA (1986) has
classified HCE as a class C carcinogen (possible human
carcinogen) , based on the observation of carcinomas in one mouse
strain after oral exposure (NCI, 1978) . The data are judged to
be sufficient for Tier 1 HCC derivation.
In a NCI study (NCI, 1978) , Osborne- Mendel rats and B6C3F1
mice were orally intubated with HCE in corn oil. Groups of 50
rats per sex per dose were administered HCE over a 78 -week period
with an exposure protocol involving intermittent treatment -free
intervals. The time -weighted- average doses were 212 or 423
mg/kg/day. The rats were then observed for an additional 33-34
weeks. Groups of 50 mice per sex per dose were administered HCE
5 days per week for 78 weeks at time -weighted- average doses of
590 or 1179 mg/kg/day, and were then observed for an additional
12-13 weeks. Due to an unusually high mortality rate among the
male control mice, the results in treated groups were compared
against both the vehicle control group from this study as well as
a pooled vehicle control group from several concurrent studies.
A statistically significant increase in the incidence of
hepatocellular carcinoma was reported in both sexes of the mice
(only males exhibited a dose -related trend) while tumorigenicity
was not observed in rats of either sex. The increased incidence
was significant by the Cochran-Armitage test for both sexes of
mice against both control groups and by the Fisher exact tests
for both sexes as compared to the pooled controls. Survival of
low- and high- dose male and female rats in this study was reduced
compared with that of the vehicle controls .
Because findings from NCI (1978) in rats were inconclusive,
additional studies on toxicity and carcinogenesis were conducted
in F344/N rats by administering HCE in corn oil by gavage to
groups of males and females for 2 years (NTP, 1989) . HCE was
administered 5 days/week in corn oil by gavage at 0, 10 or 20
mg/kg bw to groups of 50 male rats, and at 0, 80 or 160 mg HCE/kg
bw to groups of 50 female rats. The incidence of renal adenomas
and carcinomas alone and in combination increased in the high
dose male group. One of the carcinomas in the high dose group
metastasized to the lung. No compound -related neoplasms were
observed in females. The incidence of pheochromocytomas of the
adrenal gland in low dose male rats was significantly greater
than that in vehicle controls, and the incidence for both dosed
44
-------
groups were greater than the mean historical control incidence
rates. The renal lesions were considered by NTP to be indicative
of HCE carcinogenicity while the pheochromocytomas were judged to
be supportive evidence for carcinogenic effects. On the basis of
these data, NTP concluded that there was clear evidence of
carcinogenicity for HCE in the male rat and no evidence of
carcinogenicity in female rats. Renal tubule hyperplasia was
observed at an increased incidence in high dose male rats. These
lesions have been described as characteristic of the hyaline
droplet nephropathy that is associated with an accumulation of
liver -generated a2>l- globulin in the cytoplasm of tubular
epithelial cells (NTP, 1989) . Using this assumption, it can be
hypothesized that the male rat renal tumors were a secondary
effect to hyaline droplet formation and that they may not be
relevant to human risk assessment.
The Tier 1 Human Cancer Criteria for HCE are derived from
the slope factor of 1.4 E-2 (mg/kg/d)"1 based on a dose -response
data- set for hepatocellular carcinoma induction in male mice from
the NCI study (NCI, 1978; EPA, 1986).
RAD = Risk Level = _ 1 x IP'5 _
ql* 1.4 x 10 -2 (mg/kg/d)-1
= 7.14 x ICT* mg/kg/d
Drinking Water Sources:
HCV = _ RAD x BW _
WCd + [ (FCnj x BAF.^) + (FC^ x
7.14 x 10"* mcr/ka/d x 7P ka
2 1/d + [(0.0036 x 371) + (0.0114 x 532)]
= 5.3 ug/L
Non-Drinking Water Sources:
HCV = _ RAD x BW _
WCr + [(FCTu X BAF^ + (FC™ X BAF^) ]
« _ 7.14 x 10^ ma/kQ/d x 70 ko _
0.01 1/d + [(0.0036 x 371) + (0.0114 x 532)]
= 6.7 ug/L
References :
National Cancer Institute (NCI). 1978. Bioassay of
Hexachloroethane- for Possible Carcinogenicity. NCI
Carcinogenesis Technical Report Series No. 68, NCI-CG-TR-68, DHEW
Publication No. (NIH) 78-1318.
45
-------
National Toxicology Program (NTP). 1989. Toxicology and
Carcinogenesis Studies of Hexachloroethane (CAS No. 67-72-1) in
F344/N Rats (Gavage Studies). NTP Technical Report. NTP-TR-361,
NIH/PUB-89-2816, Order No. PB90-170895, 117 pp.
U.S. Environmental Protection Agency (EPA). 1986. Integrated
Risk Information. System (IRIS database). Chemical file for
hexachloroethane (67-72-1). Verification Date 7/23/86. Last
Reviewed 7/23/86.
46
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GREAT LAKES WATER QUALITY INITIATIVE
TIER I HUMAN HEALTH CRITERIA FOR
LINDANE
(GAMMA-HEXACHLOROCYCLOHEXANE)
CAS NO. 58-89-9
Tier* 1 Human Noncftnccir Grit or 3. on
A review of. the available literature indicates that the most
appropriate study for the derivation of the HNV for lindane is a
subchronic study conducted by Zoecon Corporation (1983) as
evaluated by EPA (1991) and summarized by EPA (1986) . In this
study, Wistar KFM-Ham (outbred) SPF rats (20/sex/dose) were
administered 0, 0.2, 0.8, 4, 20 or 100 ppm lindane in the feed.
Fifteen animals/sex/group were sacrificed after 12 weeks. The
remaining rats were fed the control diet for an additional six
weeks before sacrifice. Rats exposed to 20 and 100 ppm lindane
had a greater incidence of liver hypertrophy, kidney tubular
degeneration, hyaline droplets, tubular distension, interstitial
nephritis and basophilic tubules than did the controls. The
NOAEL for this study was 4 ppm. This dose was estimated to be
equivalent to 0.29 mg/kg/d for the male and 0.33 mg/kg/d for the
female rats.
Two chronic studies which examined the effects of lindane on
rats and dogs were cited by EPA (1986) . A two-year study by
Fitzhugh (1950) reported a NOAEL of 2.5 mg/kg/d in Wistar rats
with liver weights and liver damage evaluated as the endpoints.
In a two-year study in beagle dogs, Rivett et al. (1978) reported
a NOAEL of 1.6 mg/kg/d for liver toxicity.
A review of the database on developmental and reproductive
effects of lindane suggests that these effects may occur at
levels higher than the NOAEL calculated in the study conducted by
Zoecon Corporation (1983). Palmer et al. (1978a) found no
adverse effects on reproductive function and development
following exposure of female rats to lindane in the feed at
levels of 1.25, 2.5 and 5 mg/kg/d for three generations. Khera
et al. (1979) found no reproductive effects in Wistar rats
exposed to lindane at levels ranging from 6.25 to 25 mg/kg from
the 6th to the 15th day of gestation. No adverse effects were
found in a teratogenicity study on pregnant rabbits fed lindane
on gestation days 6-18 at levels of 5, 10 and 15 mg/kg (Palmer et
al., 1978b) . However, Sircar and Lahiri (1989) reported that
even the lowest exposure group (3.75 mg/kg/d) of Swiss mice
receiving lindane during gestation experienced reproductive
failure.
The quality of the study conducted by Zoecon Corporation
(1983) was deemed sufficient to derive a Tier 1 HNC. The results
of studies which examine the reproductive or developmental
effects of lindane are either negative or indicative of possible
effects at doses substantially higher than the NOAEL reported by
Zoecon Corporation (1983) . Although subchronic in duration (12
weeks) , the key study is supported by chronic studies in the
47
-------
database. This study was also used by EPA (1986) to derive the
oral RfD for lindane. The HNC was derived from the female rat
NOAEL (0.33 mg/kg/d) using an uncertainty factor of 1000 to
account for interspecies variability, intraspecies differences
and subchronic exposure duration. The magnitude of this
uncertainty factor is expected to result in adequate protection
from any potential reproductive or developmental effects as well
as chronic noncancer effects.
ADE = NOAEL = 0.33 ma/kcr/d = 3.3 x 10"4 mg/kg/day
UF 1000
Where: Uncertainty Factor « 1,000, composed of:
lOx for interspecies variability
lOx for intraspecies differences
lOx for subchronic exposure duration
Drinking Water Sources:
HNV = _ ADE X BW x RSC _
WCd + [(FC^ x BAFro) + (FC™ x
- _ 3.3 x 10"* ma/ka/d x 70 ka x 0.8 _
2 1/d + [(0.0036 x 1,926) + (0.0114 x 2,636)]
- 4.7 x lo;1 ug/L
Non-Drinking Water Sources:
HNV = _ ADE x BW x RSC _
WCr + t (FCru x BAFTLj) + (PC™ x
3.3 x 1Q-4 ma/ko/d x 70 ka x 0.8
0.01 1/d + [(0.0036 x 1,926) + (0.0114 x 2,636)]
= 5.0 x 10'1 ug/L
References :
Fitzhugh, O.G., A. A. Nelson and J. P. Frawley. 1950. The
chronic toxicities of technical benzene hexachloride and its
alpha, beta and gamma isomers. J. Pharm. Exp. Ther. 100:59-66.
Khera, K.S., C. Whalen, G. Trivett and G. Angers. 1979.
Teratogenicity studies on pesticidal formulations of dimethoate,
diuron and lindane in rats. Bull. Environ. Contain. Toxicol.
22(4-5) :522-529.
Palmer, A.K., D.D. Cozens, E.J.F. Spicer and A.N. Worden. 1978a,
Effects of lindane upon reproductive function in a 3 -generation
study in rats. 10(l):45-54.
•
48
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Palmer, A.K., A.M. Bottomley, A.N. Worden, H. Frohberg and A.
Bauer. 1978b. Effect of lindane on pregnancy in the rabbit and
rat. Toxicol. 9(3):239-247.
Rivett, K.F., H. Chesterman, D.N. Kellett, A.J. Newman and A.N.
Worden. 1978. Effects of feeding lindane to dogs for periods of
up to two years. Toxicol. 9:273-289.
Sircar, S. and P. Lahiri. 1989. Lindane (gamma-HCH) causes
reproductive failure and fetotoxicity in mice. Toxicol. 59:171-
177.
U.S. Environmental Protection Agency (EPA). 1986. Integrated
Risk Information System (IRIS database). Chemical file for
lindane (58-89-9). Verification Date 1/22/86. Last Revised
3/1/88.
U.S. Environmental Protection Agency (EPA). 1991. Data
Evaluation Record (DER) for lindane. Office of Pesticide
Programs.
Zoecon Corporation. 1983. Unpublished report. MRID No.
00128356. Available from EPA. Write to FOI, EPA, Washington,
D.C. 20460.
Tier T Human Cancsr CrJ.t6ird.oii
EPA is currently reviewing the carcinogenicity for lindane.
When this review is completed, EPA will evaluate whether there is
sufficient data to derive a Tier I human cancer criterion for
lindane.
49
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GREAT LAKES WATER QUALITY INITIATIVE
TIER 1 HUMAN HEALTH CRITERIA FOR
MERCURY
CAS NO. 7439-97-6
(INCLUDING METHYLMERCURY, CAS NO. 22967-92-6)
Tj.gr 1 Human Noncflnccr Criterion
A review of- the available literature on the environmental
cycling, fate, and toxicity of mercury and mercury compounds
indicates that HNC derivation is most appropriately based upon
the human dose-response to methylmercury. Numerous reviews on
mercury toxicity (e.g., WHO, 1976; 1990; EPA, 1980; 1984a; 1984b;
1985a) describe the human dose-response relationship resulting
from food-borne exposure to methylmercury in Iraq (1971-72),
Japan (1940s thru 1960s), and elsewhere. These data are judged
to be sufficient for Tier 1 criterion derivation.
Studies of widespread human food-borne exposure to
methylmercury in fish (Minamata and Niigata, Japan) and in seed
grain (Iraq) have shown that neurological symptoms of mercury
toxicity in adults appear with blood levels of mercury in the
range of 200 to 500 ng/ml (Nordberg and Strangert, 1976; Clarkson
et al., 1976; WHO, 1976; 1990; EPA, 1980; 1984a; 1984b; 1985a).
However, there are a few studies of workers exposed
occupationally to mercury via inhalation which suggest that blood
mercury levels as low as 10-20 ng/ml may result in the
development of signs of renal dysfunction (increased proteinurea
and albuminurea) and abnormal psychomotor performance (Roels et
al., 1982; Piikivi et al., 1984; Buchet et al., 1980). The adult
LOAEL of 200 ng/ml in blood has been associated with an intake
level of 200-500 ug/d (EPA, 1980; WHO, 1990), although the human
adult population's variability in mercury elimination rate is
significantly bimodal (Clarkson et al, 1976; Nordberg and
Strangert, 1976). The human LOAEL of 200 ug/d, or 3 ug/kg/d, for
the development pf neurological effects forms the basis for the
RfD derived by EPA (1985b) and the fish consumption criteria
derived by EPA (1980). It has been estimated that less than 5%
of the adult population will experience neurological effects at
these levels (WHO, 1990).
Risk assessments by EPA (1980) and EPA (I985b) utilized a
total uncertainty factor of 10 in conjunction with the LOAEL
dose, and both stated that the LOAEL and the risk assessment
addressed the sensitivity and the adequate protection of both
pre- and postnatal exposures. EPA (1980) justified the 10-fold
uncertainty factor as an accounting for "individual differences
in habits of fish consumption and in susceptibility to the toxic
effects of methylmercury, including prenatal exposures". EPA
(1985b) justified the 10-fold uncertainty factor "to adjust the
LOAEL to what is expected to be a NOAEL. Since the effects are
seen in sensitive individuals for chronic exposure, no additional
factors are deemed necessary".
50
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For the derivation of the Tier 1 Human Noncancer Criterion,
a total uncertainty factor of 50 will be utilized. This is
composed of a 10-fold factor to adjust the adult LOAEL to a
presumed adult NOAEL and an additional 5-fold factor to protect
CNS development during the sensitive fetal life stages. The use
of a 10-fold factor for LOAEL-to-NOAEL conversion is justified by
consideration of the severity and irreversibility of the effects
at the LOAEL, the long latency of mercury effects, and the
occupational studies which suggest that the threshold may be
considerably lower than 200 ng Hg/ml blood.
An uncertainty factor of 5 is utilized to ensure that the
criterion will be protective of the fetal effects of mercury
exposure via maternal ingestion of mercury-contaminated fish.
The particular sensitivity of the fetus has been recognized in
reviews of mercury toxicity (WHO, 1976; 1990; D'ltri, 1978; EPA,
1980; I984a; 1984b; 1985a). The earliest of these assessments
(WHO, 1976) developed a dose-response relationship for the adult
which was not presented as being accurate for the more sensitive
fetal effects. It was noted that many infant victims reported
from Minamata had severe cerebral involvement (palsy and
retardation) whereas their mothers had mild or no manifestations
of poisoning. Although these observations were qualitatively
confirmed by animal studies, quantification of the difference in
the degree of sensitivity between human fetuses and adults has
been elusive. EPA (1980; 1985b) utilized a total uncertainty
factor of 10 and assumed that the resulting risk assessments were
adequately protective of fetal effects. However, WHO (1990)
reviewed the database on oral methylmercury ingestion, including
more recent studies, and made significant advances in delineating
quantitatively the greater sensitivity of prenatal exposure
relative to adult exposure. Although WHO (1990) did not
recommend a particular numeric sensitivity factor for the fetus,
their assessment sufficiently demonstrates that an additional
uncertainty factor is reasonable and prudent to help ensure
adequate protection. They concluded that adult effects occur at
a LOAEL (for 5% increased occurrence rate) of 200 ng/ml blood, or
at 50 ug/g in hair. Fetal effects on CNS development occur at a
LOAEL (5% increased occurrence rate) of 10-20 ug/g as a peak
level in maternal hair. Since the level of mercury in maternal
blood correlates to the simultaneous level in new hair growth,
the hair serves as a fairly reliable indicator of maternal blood
mercury levels during pregnancy. The data suggest that the fetal
effects LOAEL may be 2.5 to 5 times lower than the adult effects
LOAEL.
The HNC is derived from the adult LOAEL dose of 3 ug/kg/d
which is associated with the LOAEL in blood of 200 ng/ml, and an
uncertainty factor of 50. The methylmercury form is the most
significant of the mercury compounds from the standpoint of
ambient environmental mercury and human exposures and health
impacts. Aqueous concentrations of mercury, and especially
methylmercury, may be very low in ambient waters. Other forms of
mercury, such as elemental mercury or mercury (I), may be
51
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reasonably anticipated to be transformed predominantly to
methylmercury in the aquatic environment via oxidation to mercury
(II) and biomethylation. The biomethylation of inorganic mercury
and the very high propensity for methylmercury to bioaccumulate
in aquatic organisms result in a high and significant human
exposure potential (EPA, 1980; D'ltri, 1990; Annett et al.f
1975) . The various forms of mercury released to and found in the
ambient aquatic environment may be assumed to be converted
primarily to methylmercury. Therefore, the HNC is expressed as
the total recoverable mercury concentration. Finally, a body
weight of 65 kg was used instead of a body weight of 70 kg
because of the potential fetal effects of mercury exposure via
maternal ingest ion of mercury -contaminated fish.
ADE - NOAEL = 3.0 x IP'3 ma/ka/d = 6.0 x 10'5 mg/kg/day
UF 50
Where: Uncertainty Factor - 50, composed of:
lOx for use of LOAEL instead of NOAEL
5x for intraspecies differences
(protection of fetal CNS development)
Drinking Water Sources:
HNV = _ ADE x BW x RSC _
WCd + [(FCTL3 x BAF.^) + (FCru x
6.0 x IP'5 ma/ka/d x 65 kg x 0.8
2 1/d + [(0.0036 x 27,900) + (0.0114 x 140,000)]
= 1.8 x 10'3 ug/L
Non-Drinking Water Sources:
HNV = _ ADE x BW x RSC _
WCr + [(FCTL3 x BAF^) + (FCru x
6.0 x IP'5 mg/kg/d x 65 kg x 0.8
0.01 1/d- + [(0.0036 x 27,900) + (0.0114 x 140,000)]
= 1.8 x 10'3 ug/L
References :
Annett, C.S. et al. 1975. Mercury in fish and waterfowl
from Ball Lake, Ontario. J. Environ. Qual. 4(2):219- 222.
Buchet, J.P., H.- Roels, A. Bernard and R. Lauwerys, 1980.
Assessment of renal function of workers exposed to inorganic
lead, cadmium or mercury vapor. J. Occup. Med. 22:741-750.
52
-------
Clarkson, T.W., L. Amin-Zaki and S. K. Al-Tikriti. 1976. An
outbreak of methylmercury poisoning due to consumption of
contaminated grain. Federation Proceedings. 35(12):2395-2399 .
D'ltri, P.A. and P.M. D'ltri. 1978. Mercury contamination: a
human tragedy. Environmental Management. 2 (1) : 3 -1€.
D'ltri, F.M. 1990. Mercury contamination - what we have learned
since Minamata. Environmental Monitoring and Assessment, v. 16.
Nordberg, G.F. and P. Strangert. 1976. Estimations of a dose-
response curve for long-term exposure to methylmercuric compounds
in human beings taking into account variability of critical organ
concentration and biological half-time: a preliminary
communication. In: Effects and Dose-Response Relationships of
Toxic Metals. 1976. Elsevier Scientific Publishing Company.
Amsterdam, The Netherlands, p. 273-282.
Piikivi, L., H. Hanninien, T. Martelin et al. 1984.
Pyschological performance and long term exposure to mercury
vapors. Scand. J. Work. Environ. Health 10:35-41.
Roels, J., R. Lauwerys, J.P. Buchet et al. 1982. Comparison of
renal function and psychomoter performance in workers exposed to
elemental mercury. Int. Arch. Occup. Environ. Health 50:77-93.
U.S. Environmental Protection Agency (EPA). 1980. Ambient Water
Quality Criteria Document for Mercury. EPA 440/5-80-058.
U.S. Environmental Protection Agency (EPA). 1984a. Mercury
Health Effects Update: Health Issue Assessment. OHEA. EPA-
600/8-84-019F.
U.S. Environmental Protection Agency (EPA). 1984b. Health
Effects Assessment for Mercury. EPA/540/1-86/042. NTIS: PB86-
134533.
U.S. Environmental Protection Agency (EPA). 1985a. Drinking
Water Criteria Document for Mercury. Prepared for Office of
Drinking Water, by Environmental Criteria and Assessment Office.
EPA-600/X-84-178-1. Final Draft. PB86-117827.
U.S. Environmental Protection Agency (EPA). 1985b. Integrated
Risk Information System (IRIS database). Chemical file for
methylmercury (22967-97-6). Verification Date 12/2/85. Last
Revised 2/1/89.
World Health Organization (WHO). 1976. Environmental Health
Criteria 1: Mercury. WHO, Geneva.
World Health Organization (WHO). 1990. Environmental Health
Criteria 101: Methylmercury. WHO, Geneva.
53
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iTi Cyiocor
Mercury is not considered carcinogenic.
54
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GREAT LAKES WATER QUALITY INITIATIVE
TIER I HUMAN HEALTH CRITERIA FOR
METHYLENE CHLORIDE
CAS NO. 75-09-2
Tier 1 Human Noncftpccr Criterion
A review of the literature indicates that hepatic and renal
toxicities are characteristic critical effects of methylene
chloride subchronic and chronic exposure (EPA, 1989). From
animal studies on the chronic toxicity of methylene chloride, the
most appropriate basis for HNV derivation is the NOAEL from the
chronic oral rat study by the National Coffee Association (NCA,
1982; Serota, et al., 1986a). In this study, F344 rats
(85/sex/group) received nominal doses of 0, 5, 50, 125 or 250
mg/kg/day of methylene chloride via drinking water exposure for 2
years. An induction of liver toxicity in the females was
observed. Treatment-related histological alterations such as
increases in hepatocellular foci and fatty changes in the liver
were observed in rats of both sexes at nominal doses of * 50
mg/kg/day. No treatment-related effects were noted in the rats
administered the nominal dose of 5 mg/kg/day. The actual NOAEL
doses were 5.85 and 6.47 mg/kg/day for males and females,
respectively.
In addition to the rat drinking water study, Hazleton Labs
conducted a 24-month study with B6C3F1 mice for the National
Coffee Association (NCA, 1983; Serota et al., 1986b). In this
study, mice were exposed to nominal doses of 0, 60, 125, 185, and
250 mg/kg/day of methylene chloride in drinking water for up to
24 months. Dose-related hist©morphologic changes, such as
proliferative hepatic lesions and enhanced amount of Oil Red 0
positive material, were observed in groups exposed to the highest
dose of methylene chloride. The study reported a NOAEL of 185
mg/kg/day. Compared to the 5.85-6.47 mg/kg/day NOAEL in rats
(NCA, 1982; Serota et al., 1986a), this study demonstrates a wide
difference in the interspecies sensitivities to methylene
chloride-induced toxic effects.
In a 2-year inhalation toxicity and oncogenicity study by
Dow Chemical Co. (Nitschke et al., 1988), groups of Sprague-
Dawley rats (90 male and 180 female) were exposed to 0, 50, 200,
or 500 ppm methylene chloride for 6 hours/day, 5 days/week for 2
years. During the course of the study, all rats were monitored
after each exposure for signs of toxicity, changes in body weight
and food intake. Samples of liver tissue were analyzed for DNA
synthesis as indicated by 3[H]-thymidine uptake. Rats selected
for interim necropsies and all the others (at the end of the
study) were subjected to extensive gross pathologic,
histopathologic, and serum chemistry evaluation. Data on DNA
synthesis in the liver, pathology, histopathology, mortality, and
other parameters were evaluated for statistically significant
55
-------
differences between the exposed and controls groups. Pathologic
and histopathologic data of the exposed groups indicated that the
liver and kidney are the primary targets of methylene chloride
toxicity. An increased incidence of hepatocellular vacuolization
was observed in male and female rats exposed to 500 ppm of
methylene chloride. In addition, elevated numbers of
multinucleated hepatocytes were observed in female rats exposed
to 500 ppm methylene chloride. The effects of methylene chloride
at lower doses (50 and 200 ppm) were comparable with historical
controls. Responses to chemical insult leveled off by 12 months
in that the responses of female rats exposed to 500 ppm for the
first 12 months were comparable to those of female rats exposed
to the same concentration for 24 months. Based on these results,
the authors concluded that 200 ppm (706.7 mg/m3) is the NOAEL for
methylene chloride by the inhalation route. This exposure may be
converted to a daily administered dose of approximately 159
mg/kg/day, adjusting for 6 hours/day exposure and assuming that
Sprague-Dawley rats breathe approximately 0.9 m3/kg bw/day (EPA,
1988).
Burek et al. (1984) reported a 2-year inhalation study of
methylene chloride with Sprague-Dawley rats and Golden Syrian
Hamsters. In this study, rats and hamsters were exposed to 0,
500, 1500, and 3500 ppm of methylene chloride for 6 hours/day, 5
days/week for 2 years. Liver and mammary glands were the
principal target tissues of methylene chloride inhalation
toxicity in rats. Groups exposed to 500 to 3500 ppm methylene
chloride showed increased incidence of hepatocellular
vacuolization consistent with fatty changes, and the number of
multinucleated hepatocytes in the female rats was elevated.
After 18 months of exposure to the regimen, several
characteristic lesions of liver and mammary glands were
transformed to benign neoplasms (Burek et al., 1984).
The database is judged to be sufficient for Tier 1 HNC
derivation. The key study (NCA, 1982; Serota et al. 1986a)
provides a chronic oral NOAEL which is supported and supplemented
by other oral and inhalation chronic toxicity data. EPA used
this key study in the derivation of the oral RfD for risk
assessment purposes (EPA, 1985a), and to derive lifetime health
advisories for methylene chloride (EPA, 1985b). For the RfD
derivation, EPA -(1985a) used the male and female rat doses,
respectively of 52.58 and 58.32 mg/kg/day for LOAELs, and 5.85
and 6.47 mg/kg/day for NOAELs for hepatic effects (NCA, 1982;
Serota et al., 1986a). The HNC is derived from the NOAEL from
the key study, 5.85 mg/kg/day to male rats.
ADE = NOAEL = 5.85 ma/kcr/d - 5.85 x 10'2 mg/kg/d
UF 100
Where: Uncertainty Factor = 100, composed of:
lOx for interspecies variability
lOx for intraspecies differences
56
-------
Drinking Water Sources:
HNV m _ APE x BW x RSC
WCd + [
- 5.85 x IP'2 ma/ka/d x 70 ka x 0.8
2 1/d + [(0.0036 x 1) + (0.0114 x 2)]
« 1.6 x 103 ug/L
Non-Drinking Water Sources:
HNV = _ APE x BW x RSC _
WCr + [ (FCru x BAFTu) + (FC^ x
= 5.85 x IP'2 ma/ka/d x 70 kg x 0.8
0.01 1/d + [(0.0036 x 1) + (0.0114 x 2)]
= 9.0 x 10? ug/L
References :
Burek, J.D., K.D. Nitschke, T.J. Bell, D.L. Wackerle, R.C.
Childs, J.E. Beyer, D.A. Dittenber, L.W. Rampy, and M.J. McKenna.
1984. Methylene chloride: A two-year inhalation toxicity and
oncogenicity study in rats and hamsters. Fundam. Appl. Toxicol.
4:30-47.
National Coffee Association (NCA) . 1983. Twenty-Four Month
Oncogenicity Study of Methylene Chloride in Mice. Prepared by
Hazleton Laboratories America, Inc., Vienna, VA. (Unpublished).
National Coffee Association (NCA). 1982. 24-Month Chronic
Toxicity and Oncogenicity Study of Methylene Chloride in Rats.
Final Report. Prepared by Hazleton Laboratories America, Inc.,
Vienna, VA. (Unpublished) .
National Toxicology Program (NTP) . 1986. Toxicology and
Carcinogenesis Studies of Dichloromethane (Methylene Chloride)
in F344/N Rats and B6C3F1 Mice (Inhalation Studies) .
NTP-TRS-306.
Nitschke, K.D., J.D. Burek, T.J. Bell, R.J. Kociba, L.W. Rampy,
and M.J. McKenna. 1988. Methylene chloride: A two-year
inhalation toxicity and oncogenicity study in rats. Fundam.
Appl. Toxicol. -11:48-59.
Serota, D.G., A.K. Thakur, B.M. Ulland, J.C. Kirschman, N.M.
Brown, R.H. Coots and K. Morgareidge. 1986a. A two-year
drinking water study of dichlorome thane on rodents. I. Rats.
Food Chem. Toxicol. 24:951-958.
57
-------
Serota, D.G., A.K. Thakur, B.M. Ulland, J.C. Kirschman, N.M.
Brown, R.H. Coots and K. Morgareidge. 1986b. A two-year
drinking water study of dichloromethane on rodents. II. Mice.
Food Chem. Toxicol. 24:959-964.
U.S. Environmental Protection Agency (EPA). 1989. • Health
Effects Assessment for Methylene Chloride. EPA/600-8-89-092.
Environmental Criteria and Assessment Office (ORD), Cincinnati,
OH. PB90-142449.
U.S. Environmental Protection Agency (EPA). 1988.
Recommendations for and Documentation of Biological Values for
Use in Risk Assessment. PB88-179874.
U.S. Environmental Protection Agency (EPA). 1985a. Integrated
Risk Information System (IRIS database). Chemical file for
methylene chloride (75-09-2). Verification date 11/6/85. Last
reviewed 11/6/85.
U.S. Environmental Protection Agency (EPA). 1985b. Healtyh
Advisory for Dichloromethane. Prepared by the Office of Drinking
Water, Washington, D.C. PB86-118338.
Tier i Human Cancer Criterion
Methylene chloride is a class B2 carcinogen (a probable
human carcinogen) according to the EPA weight-of-evidence
classification of carcinogenic chemicals (EPA, 1989a). The
classification rationale is based on sufficient evidence from
animal carcinogenicity. Two epidemiological studies on chemical
factory workers exposed to methylene chloride (Ott et al.. 1983;
Friedlander et al., 1978; Hearne et al., 1987) are inconclusive
on the human carcinogenicity of methylene chloride. Review of
these epidemiological studies and updated evaluation of the
cohorts still provide inadequate evidence of human
carcinogenicity .(EPA, 1989b) . Experimental carcinogenesis
studies indicate that exposure to methylene chloride by the oral
route resulted in a significant increase in the incidence of
hepatocellular carcinoma and neoplastic nodules in female F344
rats (NCA, 1982; Serota et al., 1986a) and male B6C3P1 mice (NCA,
1983; Serota et al, 1986b). Inhalation studies with methylene
chloride produced an increased incidence of mammary tumors in
both sexes of Sprague-Dawley (Burek et al., 1980, 1984) and F344
rats (NTP, 1986). The data are judged to be sufficient for Tier
1 HCC derivation-.
The carcinogenic effects of methylene chloride via the oral
route were investigated in two separate 2-year studies sponsored
by the National Coffee Association (NCA, 1982, 1983; Serota et
al., 1986a, 1986b). In the 1982 study, groups of 85 F344 rats of
either sex received nominal doses of 5, 50, 125, or 250 mg/kg/day
of methylene chloride in drinking water. Female rats receiving
58
-------
50 and 250 mg/kg/day had a significantly increased incidence of
combined hepatocellular carcinoma and neoplastic nodules in
comparison to matched controls. Male rats, however, did not show
an increased incidence of liver tumors. A dose-dependent,
statistically significant increase in the incidence of salivary
gland sarcoma was observed in male rats. A dose-related increase
in the average number of benign mammary tumors was observed in
female rats. The increased incidence of mammary tumors was
observed in male rats, albeit to a lesser degree.
The National Coffee Association in its subsequent study
(NCA, 1983; Serota et al., 1986b) exposed B6C3F1 mice of either
sex to 0, 60, 125, 185, or 250 mg/kg/day methylene chloride in
drinking water. A statistically significant increase in the
incidence of combined hepatocellular carcinoma and neoplastic
nodules was observed in male mice exposed to 125 and 185
mg/kg/day. However, only a marginal increase in the incidence of
tumorigenesis and reduced average survival time was observed in
the 250 mg/kg/day group.
Quantitative cancer risk estimates of methylene chloride are
based on NTP inhalation studies in rats and mice (NTP, 1986). In
this study, groups of 50 male and female F344/N rats and B6C3F1
mice were exposed to 0, 1000, 2000, and 4000 ppm (rats), and 0,
2000, and 4000 ppm (mice) for 6 hrs/day, 5 days/week for 102
weeks. Female rats, and to a lesser degree male rats,
demonstrated a statistically significant increase in the
incidence of mammary gland neoplasms. In mice, methylene
chloride elicited an enhanced combined incidence of
hepatocellular adenomas and carcinomas in the male (22/50, 24/49,
33/49) and female (3/50, 16/48, and 40/48) mice. Similarly, both
male and female mice displayed an increased incidence of
alveolar/bronchiolar adenomas and carcinomas (NTP, 1986).
In an inhalation study reported by Dow Chemical Company
(Burek et al., 1980, 1984), Sprague-Dawley rats and Syrian Golden
hamsters of both sexes were exposed to 0, 500, 1500, or 3500 ppm
methylene chloride for 6 hrs/day, 5 days/week for 24 months. A
statistically significant increased incidence of benign tumors in
female hamsters exposed to 3500 ppm was attributed to increased
longevity in that group. A statistically significant increase in
salivary gland sarcoma was observed in male rats exposed to 3500
ppm methylene chloride. The finding of methylene chloride-
induced salivary gland tumors in male rats is complicated by the
observation that these rats had apparently contracted a viral
disease, sialodacryoadentitis, in the salivary glands during the
earlier phase of the exposure regimen (Burek et al., 1980, 1984).
Based on these uncertainties, experimental results from this
study were considered inconclusive on the carcinogenicity of
methylene chloride. In a subsequent inhalation study by Dow
Chemical Company (Nitschke et al., 1982), limited evidence of
mammary fibroma/fibrosarcoma was observed in male and female rats
exposed to 0, 50, 200, or 500 ppm of methylene chloride for 2
years.
59
-------
EPA (1989b) derived a recommended oral slope factor from the
arithmetic mean of two slope factors derived from the induction
of liver tumors in female mice by inhalation (NTP, 1986) and in
male mice by drinking water exposure (NCA, 1983; Serota et al.,
1986b) . These individual slope factors were 2.6 x 10"3 (mg/kg/d)'1
and 1.2 x 1CT2 (mg/kg/d)-1, respectively (EPA, 1989b) . This
approach recommended by EPA (1989b) is utilized for Tier 1 HCC
derivation, utilizing an arithmetic mean slope factor of 7.3 x
1C'3 (mg/kg/d)-1.
RAD - Risk Level • 1 x IP'5
ql* 7.3 x 10° (mg/kg/d)'1
- 1.37 x 10'3 mg/kg/d
Drinking Water Sources:
HCV . RAD x BW
WCd + [(FCnj x BAF-nj) + (FC^ x BAF^) ]
- 1.37 x IP'3 ma/kcr/d x 70 ka
2 1/d + [(0.0036 x 1) + (0.0114 x 2)]
= 47 ug/L
Non-Drinking Water Sources:
HCV = _ RAD x BW _
WC, + [(FC^, x BAF.^) + (FC^ x
1.37 x IP'3 ma/kcr/d x 70 ka
0.01 1/d* + [(0.0036 x 1) + (0.0114 x 2)]
= 2.6 x 103 ug/L
References :
Burek, J.D., K.D. Nitschke, and T.J. Bell. 1980. Methylene
Chloride: A Two- Year Inhalation Toxicity and Oncogenicity Study
in Rats and Hamsters. Toxicology Research Laboratory, Health and
Environmental Sciences, Dow Chemical Company, Midland, MI.
Burek, J.D., K.D. Nitschke, T.J. Bell, D.L. Wackerle, R.C.
Childs, J.E. Beyer, D.A. Dittenber, L.W. Rampy, and M.J. McKenna.
1984. Methylene chloride: A two-year inhalation toxicity and
oncogenicity study in rats and hamsters. Fundam. Appl. Toxicol.
4:30-47.
Friedlander, B.R.. , F.T. Hearne, and S. Hall. 1978.
Epidemiologic investigation of employees chronically exposed to
60
-------
methylene chloride -- mortality analysis. J. Occup. Med.
20:657-666.
Hearne, F.T., F.-Grose, J.W. Pifer, B.R. Friedlander, and R.L.
Raleigh. 1987. Methylene chloride mortality study: Dose-
response characterization and animal model comparison. J. Occup.
Med. 29:217-228.
National Coffee Association (NCA). 1983. Twenty-Four Month
Oncogenicity Study of Methylene Chloride in Mice. Prepared by
Hazleton Laboratories America, Inc., Vienna, VA. (Unpublished).
National Coffee Association (NCA). 1982. 24-Month Chronic
Toxicity and Oncogenicity Study of Methylene Chloride in Rats.
Final Report. Prepared by Hazleton Laboratories America, Inc.,
Vienna, VA. (Unpublished).
Nitschke, K.D., J.D. Burek, T.J. Bell, L.W. Rampy, and M.G.
McKenna. 1982. Methylene Chloride: A Two-Year Inhalation
Toxicity and Oncogenicity Study. Toxicology Research Laboratory,
Health and Environmental Sciences, Dow Chemical Company. Midland,
MI. (Final Report).
National Toxicology Program (NTP). 1986. Toxicology and
Carcinogenesis Studies of Dichloromethane (Methylene Chloride)
in F344/N Rats and B6C3F1 Mice (Inhalation Studies).
NTP-TRS-306.
Ott, M.G. L.K. Skory, B.B. Holder, J.M. Bronson and P.R.
Williams. 1983.. Health evaluation of employees occupationally
exposed to methylene chloride -- mortality. Scanc. J. Work
Environ. Health. 9:8-16.
Serota, D.G., A.K. Thakur, B.M. Ulland, J.C. Kirschman, N.M.
Brown, R.H. Coots and K. Morgareidge. 1986a. A two-year
drinking water study of dichloromethane on rodents. I. Rats.
Food Chem. Toxicol. 24:951-958.
Serota, D.G., A.K. Thakur, B.M. Ulland, J.C. Kirschman, N.M.
Brown, R.H. Coots and K. Morgareidge. 1986b. A two-year
drinking water study of dichloromethane on rodents. II. Mice.
Food Chem. Toxicol. 24:959-964.
U.S. Environmental Protection Agency (EPA). 1985. Addendum to
the Health Assessment Document for Dichloromethane (Methylene
Chloride). Updated Carcinogenicity Assessment. Prepared by the
Carcinogen Assessment Group, OHLA, Washington, DC. EPA
600/8-B2/004FF. .
U.S. Environmental Protection Agency (EPA). 1989a. Risk
Assessment Guidance For Superfund, Vol 1., Human Health
61
-------
Evaluation Manual (Part A). EPA/540/1-89/002. Office of
Emergency and Remedial Responses (Superfund), Washington, D.C.
U.S. Environmental Protection Agency (EPA). 1989b. Integrated
Risk Information System (IRIS database). Chemical file for
dichloromethane (75-09-2). Verification Date 4/6/89. Last
Reviewed 4/6/89.'
62
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GREAT LAKES WATER QUALITY INITIATIVE
TIER I HUMAN HEALTH CRITERIA FOR
POLYCHLORINATED BIPHENYLS (PCBS)
CAS NO. 1336-36-3
Tier "* Truman Noncancer Criterion
The database is judged insufficient for Tier 1 Human
Noncancer Criterion development.
Tier 1 Human Cancer
PCBs (as a class) have sufficient carcinogen! city weight- of -
evidence for a B2 classification (probable human carcinogen)
based on the induction of hepatocellular carcinomas in three
strains of rats and two strains of mice and inadequate yet
suggestive evidence of excess risk of liver cancer in humans
(EPA, 1987) . The data are judged sufficient for Tier 1 HCC
derivation. Although animal feeding studies demonstrate the
carcinogenicity of commercial PCB preparations, it is not known
which of the PCB congeners in such mixtures are responsible for
these effects. EPA (1987) developed a carcinogenicity risk
assessment for PCBs with a slope factor derived from Aroclor 1260
data, clearly stating the intent that the assessment be
considered representative for all PCB mixtures. The application
of this approach- to regulatory programs is a prudent approach to
ensure adequate protection of public health.
A review of the available carcinogenicity data indicates
that the most appropriate studies for quantitative cancer risk
assessment are the bioassays of Kimbrough et al (1975) and
Norback and Weltman (1985) . These studies utilized different rat
strains -- Sherman rats in the Kimbrough et al (1975) study,
Sprague-Dawley rats in the Norback and Weltman (1985) study --
but otherwise had several similarities. Both utilized large
numbers of animals in chronic Aroclor 1260 feeding studies with
only one exposure group. Dosed groups received 100 ppm for 630
days in the bioassay by Kimbrough et al. (1975), while Norback
and Weltman (1985) administered 100 ppm for 16 months followed by
a 50 ppm diet for an additional 8 months, then a basal diet for 5
months. The predominant neoplastic effect in each study was the
increased incidence of hepatocellular neoplasms in female rats.
Using the linearized multistage procedure, EPA (1987)
estimated slope factors of 7.7 (mg/kg/d) ~ and 3.9 (mg/kg/d)
from the data of* Norback and Weltman (1985) and Kimbrough et al.
(1975), respectively. The larger of these slope factors, 7.7
(mg/kg/d) ~ , was selected by EPA (1987) as the preferred slope
factor estimate.
Although the Norback and Weltman (1985) study included a
test protocol of partially hepatectomizing some of the animals,
EPA (1987) noted that the study had favorable qualities. The rat
strain used (Sprague-Dawley) is known to have a low incidence of
63
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spontaneous hepatocellular neoplasms, the study duration spanned
the natural life of the animal, and concurrent morphologic liver
studies showed the sequential progression of liver lesions to
hepatocellular carcinomas. Extrapolation modeling utilized a
female rat liver tumor incidence rate of 45/47 in the dosed
group. This includes 7 animals which had earlier undergone
partial hepatectomy, and the liver tumor incidence for this
subgroup was unreported. Exclusion of this group would have very
little impact on the resulting slope factor, and the tumor
promoting effect of the partial hepatectomization should be
minimal (Hiremath, 1991) . The Tier 1 Human Cancer_ Criterion for
PCBs is based on the slope factor of 7.7 (mg/kg/d)" derived from
the rat bioassay of Norback and WeItman (1985).
RAD - Risk Level - 1 x IP'3 - 1.30 x 1CT6 mg/kg/d
ql* 7.7 (mg/kg/d)-1
Drinking Water Sources:
HCV = RAD x BW
WCd + [ (FCro x BAFnj) + (PC™ x BAF^) ]
= 1.30 x IP"6 ma/ka/d x 70 ka
2 1/d + [(0.0036 x 520,900) + (0.0114 x 1,871,000)]
- 3.9 x 10* ug/L
Non-Drinking Water Sources:
HCV = RAD x BW
WCr + [ (FCrLj x BAF-TLg) + (FCn, x BAFTU) ]
= 1.30 x IP"6 ma/ka/d x 70 ko
0.01 1/d. + [(0.0036 x 520,900) + (0.0114 x 1,871,000)]
= 3.9 x 10-6 ug/L
References:
Hiremath, C. 1991. Toxicologist, U.S. EPA Office of
Research and Development. Personal communication with R. Sills,
Michigan Department of Natural Resources.
Kimbrough, R.D. et al. 1975. Induction of liver tumors in
Sherman strain female rats by Aroclor 1260. J. National Cancer
Institute. 55(6):1453.
Norback. D. and R.H. Weltman. 1985. Polychlorinated biphenyl
induction of hepatocellular carcinomas in the Sprague-Dawley rat.
Env. Health Persp. 60:97-105.
64
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U.S. Environmental Protection Agency (EPA). 1987. Integrated
Risk Information' System (IRIS database). Chemical file for
polychlorinated biphenyls (PCBs) (1336-36-3). Verification Date
4/22/87. Last Revised 1/1/90.
65
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GREAT LAKES WATER QUALITY INITIATIVE
TIER 1 HUMAN HEALTH CRITERIA FOR
2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN (2,3,7,8-TCDD).
CAS NO. 1746-01-6
Of the many subacute and chronic studies available for
2,3,7,8-TCDD, a few stand out as supporting Tier 1 criterion
derivation. In a two-year toxicity and oncogenicity study, rats
were administered doses of 0, 0.001, 0.01 and 0.1 ug/kg bw/day of
2,3,7,8-TCDD via diet (Kociba et al., 1978). Animals given the
high dose exhibited increased mortality, decreased weight gain,
slight depression of erythroid parameters, increased urinary
excretion of porphyrins and delta-aminolevulinic acid and
increased serum levels of certain enzymes. Histopathologic or
gross effects were seen in liver, lymphoid, lung and vascular
tissues. An increased tumor incidence was also seen. Similar
effects, but to a lesser degree, were seen in mid-dose animals.
A NOAEL of 0.001*ug/kg/day (1 ng/kg/day) was reported in this
study.
A NOAEL of 0.001 ug/kg bw/day via feed exposure was also
reported in a three-generation rat reproduction study (Murray et
al., 1979). At 0.1 ug/kg/day, decreases in F0 generation
fertility and F, generation litter size were reported. At 0.01
ug/kg/day, significant decreases in fertility were seen in the Fl
and F2 generations; other effects included decreased litter size
at birth, decreased gestational survival and decreased neonatal
growth and survival. The reproductive capacity of the low dose
ra^s did not appear to be significantly affected in any
generation. However, a reevaluation of these data using
different statistical methods indicated that both lower dose
levels resulted in significant reductions in offspring survival
indices, increases in liver and kidney weight of pups, decreased
thymus weight of pups, decreased neonatal weights and increased
incidence of dilated renal pelvis (Nisbet and Paxton, 1982) .
Nisbet and Paxton (1982) concluded that 0.001 ug/kg/day (1
ng/kg/day) was not a NOEL in the Murray et al. (1979) study.
Kimmel (1988) considered the data of Murray et al. (1979) to be
suggestive of a pattern of decreased offspring survival and
increased offspring renal pathology even at 0.001 ug/kg/day,
although the pooling of data from different generations by Nisbet
and Paxton (1982) was considered biologically inappropriate.
Studies by Schantz et al. (1979) and Allen et al. (1979)
suggest that rhesus monkeys are more sensitive to 2,3,7,8-TCDD
than rats. When, monkeys were administered 50 ppt 2,3,7,8-TCDD in
feed for 7 to 20 months, decreases in fertility, increases in
abortions and other toxic effects (alopecia, hyperkeratosis,
weight loss, decreased hematocrit and white blood cell count and
increased serum levels of SGPT) were noted. The 50 ppt dietary
66
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residue level corresponds to a daily dose of 1.5 ng/kg bw/day
(EPA, 1984). Therefore, 1.5 ng/kg/day can be considered a LOAEL
for rhesus monkeys from these studies.
In a continuation of the rhesus monkey studies by Schantz et
al. (1979) and Allen et al. (1979), Bowman et al. (1989a, 1989b)
have evaluated the effects of 5 and 25 ppt 2,3,7,8-TCDD in feed
on reproduction and on behavior, respectively. Breeding of the
animals after 7 and 24 months of exposure resulted in impaired
reproductive success at 25 ppt but not at 5 ppt (approximately
0.67 and 0.13 ng/kg bw/day, respectively). The exposures were
discontinued after 4 years, and a third breeding ten months post-
exposure did not indicate reproductive impairment (Bowman et al.,
1989a). The offspring from these breeding experiments were
evaluated for development and behavioral effects utilizing
several testing methods (Bowman et al., 1989b). Although there
were no significant effects of TCDD exposure on birth weight,
growth, or physical appearance of the offspring, some behavioral
test results were interpreted to be indicative of TCDD effects.
These included alterations in the social behavior between the
mothers and their infants and of peer groups of the offspring
after weaning. However, the study groups were very limited in
size and the statistical and biological significance of the
findings are unclear. This study may be interpreted to provide
only suggestive evidence of possible behavioral effects. The
reproduction study of Bowman et al. (1989a) provides much clearer
evidence of a LOAEL at 25 ppt (0.67 ng/kg/day) and a NOAEL at 5
ppt (0.13 ng/kg/day).
The EPA has used the equivocal evidence for a rat LOAEL at
1 ng/kg/day, supported by an unequivocal rhesus monkey LOAEL at
1.5 ng/kg/day, in the development of an Acceptable Daily Intake
(ADI) (EPA. 1984; 1985a) and Drinking Water Equivalent Level
(DWEL) (EPA, 1985b; 1990). In light of the more recent rhesus
monkey study of Bowman et al. (1989a), there is improved
resolution of the threshold for the sensitive effect of
reproductive impairment in this species. The Human Noncancer
Criterion is based on the NOAEL of 0.13 ng/kg/day (1.3 x 10'7
mg/kg/d) for reproductive effects from this study. The entirety
of the rhesus monkey studies, supported by the evidence in rats
cited above, is judged sufficient for Tier 1 criterion
development.
ADE = 1.3 X 1Q:7 ma/kcr/d = 1.3 x 10'9 mg/kg/d
100
Where: Uncertainty Factor = 100, composed of:
lOx for interspecies variability
lOx for intraspecies differences
Drinking Water Sources:
67
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HNV = APE x BW x RSC
WCd + [{FCTL3 x BAFra) + (PC™ x
= 1.30 x IP'9 mo/ka/d x 70 ka x 0.8
2 1/d + [(0.0036 x 48,490) + (0.0114 x 79,420)]
= 6.7 x 10;8 ug/L
Non-Drinking Water Sources:
HNV » APE x BW x RSC
WC, + [(FCn.3 x BAFTu) + (FC^ x BAF^) ]
- 1.30 x IP'9 ma/ka/d x 70 ka x 0.8
0.01 1/d + [(0.0036 x 48,490) + (0.0114 x 79,420)]
= 6.7 x 10:* ug/L
References:
Allen, J.R. et al. 1979. Reproductive effects of
halogenated aromatic hydrocarbons on nonhuman primates. Ann. NY
Acad. Sci. 320:419-425.
Bowman, R.E., et. al. 1989a. Chronic dietary intake of
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) at 5 or 25 parts per
trillion in the monkey: TCDD kinetics and dose-effect estimate
of reproductive toxicity. Chemosphere. 18(1-6): 243-252.
Bowman, R.E., et al. 1989b. Behavioral effects in monkeys
exposed to 2,3,7,«-TCDD transmitted maternally during gestation
and for four months of nursing. Chemosphere. 18(1-6):235-242.
Kimmel, G.L. 1968. Appendix C. Reproductive and
DevelopmentalToxicity of 2,3,7,8-TCDD. Reproductive Effects
Assessment Group, OHEA/ORD, EPA. In: EPA. 1988. A Cancer
Risk-Specific Dose Estimate for 2,3,7,8-TCDD. Appendices A-F.
Review Draft. EPA/600/6-88/007Ab.
Kociba, R. J. et al. 1978. Results of a two-year chronic
toxicity and oncogenicity study of 2,3,7,8- tetrachlorodibenzo-p-
dioxin in rats. Toxicol. Applied Pharmacol. 46:279-303.
Murray, F. J. et al. 1979. Three-generation reproduction study
of rats given 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the
diet. Toxicol. Applied Pharmacol. 50:241-252.
Nisbet, I.C.T. and M.B. Paxton. 1982. Statistical aspects of
three-generation studies of the reproductive toxicity of TCDD and
2,4,5-T. The American Statistician. 36(3):290-298.
68
-------
Schantz, S. L. et al. 1979. Toxicological effects produced in
nonhuman primates chronically exposed to 50 ppt TCDD. Toxicol.
Applied Pharmacol. 48:A180. (Abstract No. 360).
U.S. Environmental Protection Agency (EPA). 1984. Ambient Water
Quality Criteria for 2,3,7,8-Tetrachlorodibenzo-p-dioxin. Office
of Water Regulations and Standards. EPA 440/5-84-007.
U.S. Environmental Protection Agency (EPA). 1985a. Health
Assessment Document for Polychlorinated Dibenzo-p-dioxins.
Office of Health and Environmental Assessment. EPA/600/8-
84/014F.
U.S. Environmental Protection Agency (EPA). 1985b. Drinking
Water Criteria Document for 2,3,7,8- Tetrachlorodibenzo-p-dioxin.
ECAO/ODW. EPA-600/X-84-194-1. PB 86-117983.
U.S. Environmental Protection Agency (EPA). 1990. 55 Federal
Register No. 143. Wednesday, July 25, 1990. National Primary
and Secondary Drinking Water Regulations; Synthetic Organic
Chemicals and Inorganic Chemicals. Proposed rule.
Tier i Human Pantser Criterion
The EPA (1984) evaluated the available epidemiological and
animal bioassay data on the potential carcinogenicity of 2,3,7,8-
TCDD. They determined that some case -control studies provide
limited evidence for the human carcinogenicity of phenoxy acids
and/or chlorophenols , which contain impurities including 2,3,7,8-
TCDD. They concluded that the evidence for the human
carcinogenicity of 2, 3, 7, 8 -TCDD based on the epidemiologic
studies is only suggestive due to the difficulty of evaluating
the risk of 2, 3, 7, 8 -TCDD exposure in the presence of the
confounding effects of phenoxy acids and/or chlorophenol .
Recently published epidemiology studies may be interpreted to
provide suggestive evidence of carcinogenicity (Zober et al.,
1990; Fingerhut et al., 1991). The potential use of these new
studies for quantitative risk assessment has not yet been fully
explored. With regard to animal bioassays, the EPA (1984)
concluded that several rodent studies establish that 2 ,3, 7, 8 -TCDD
is an animal carcinogen in multiple species and organs and is
probably carcinogenic in humans. The weight of evidence of
carcinogenicity is sufficient for Group B2 classification
(probable human carcinogen) , and satisfies the database
requirements for Tier 1 criterion derivation.
Among the carcinogenicity bioassays, NTP conducted bioassays
with both Osborne- Mendel rats and B6C3F1 mice (NTP, 1982a) .
Groups of 50 mice and 50 rats of each sex were given 2, 3, 7, 8 -TCDD
in corn oil -acetone by gavage twice per week for 104 weeks.
Doses of 0, 0.01, 0.05 or 0.5 ug/kg/week were administered to
69
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rats and male mice while female mice received 0, 0.04, 0.2 or 2.0
ug/kg/week. Controls consisted of 75 rats and 75 mice of each
sex. Animals were killed at weeks 105-107. 2,3,7,8-TCDD caused
an increased, dose-related incidence of follicular-cell adenomas
or carcinomas of the thyroid in male rats. A significant
increase in subcutaneous tissue fibromas was also seen in high-
dose males. High-dose female rats exhibited increased incidence
of hepatocellular carcinomas and neoplastic nodules, subcutaneous
tissue fibrosarcomas and adrenal cortical adenomas. In male and
female mice, 2,3,7,8-TCDD induced an increased dose-related
incidence of hepatocellular carcinomas. High-dose female mice
also exhibited increased incidence of thyroid follicular-cell
adenomas.
In a dermal study also conducted under contract for NTP
(NTP, I982b), 30 male and 30 female Swiss Webster mice were
treated with 2,3,7,8-TCDD in acetone for 3 days/week for 104
weeks. Doses of 0.005 ug and 0.001 ug 2,3,7,8-TCDD were
administered to the clipped backs of males and females,
respectively. A similar group was pretreated with one
application of 50 ug dimethylbenzanthracene (DMBA) one week
before 2,3,7,8-TCDD administration. 2,3,7,8-TCDD induced a
statistically significant increase of fibrosarcomas in the
integumentary system of females given both 2,3,7,8-TCDD alone and
following a single application of DMBA.
Van Miller et al. (1977) administered diets containing 0,
0.001, 0.005, 0.05, 1, 50, 500 and 1000 ppb 2,3,7,8-TCDD to
groups of 10 male Sprague-Dawley rats. Animals received the
diets for 78 weeks and were then placed on control feed until
they were killed, at week 95. All rats fed the higher
concentrations (1-1,000 ppb) died early. A variety of tumors
were produced and the total number of animals with tumors
generally increased, but the small number of animals limits the
value of the data.
Kociba et al. (1978) administered 2,3,7,8-TCDD via the diet
to groups of 50 male and 50 female Sprague-Dawley rats for 2
years. Control groups consisted of 86 animals of each sex. The
doses administered were 0, 0.001, 0.01 and 0.1 ug/kg/day.
2,3,7,8-TCDD induced an increased incidence of hepatocellular
carcinomas and hepatocellular hyperplastic (neoplastic) nodules
in female rats at the two highest dose levels. The highest dose
of 2,3,7,8-TCDD also induced an increase in the incidence of
stratified squamous cell carcinomas of the hard palate and/or
nasal turbinates in both males and females, squamous cell
carcinomas of the tongue in males and squamous cell carcinomas of
the lungs in females.
Kociba et al. (1978) is chosen as the basis for quantitative
cancer risk assessment. The Kociba study found that the
principal target organ for 2,3,7,8-TCDD-induced tumors was the
liver in female rats, demonstrating a dose-related statistically
significant increase of hepatocellular carcinomas and
hyperplastic (neoplastic) nodules. For quantitative risk
assessment, the data were adjusted for early mortality by
70
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eliminating those animals that died during the first year of the
study. Also, in the mid-dose group, two of the reported 20
females with tumors had both nodules and carcinomas; 18 affected
animals were used as the input for the dose group. Using the
linearized multistage model, the resulting slope factor for
2,3,7,8-TCDD is 1.51 x 105 (mg/kg/day)'l. However, an independent
pathologist (Squire) was engaged by EPA to reevaluate the
histopathologic slides from the Kociba study (EPA, 1984). Squire
reported higher tumor incidence than Kociba, generating a
slightly higher slope factor of 1.61 x 10s (mg/kg/day)'1. EPA
(1984) used an average of the two slope factors, 1.56 x 105
(mg/kg/day)"1, to generate surface water criteria.
In March 1990 a panel of seven independent pathologists
referred to as the Pathology Working Group (PWG) blindly
reevaluated the female rat liver slides from Kociba et al.
(1978). Liver lesions were classified according to the National
Toxicology Program's 1986 liver tumor classification scheme
(Sauer, 1990; Goodman and Sauer, 1992). Using the linearized
multistage model, the liver tumor incidence rates reported by the
PWG result in a slope factor of 5.1 x 104 (mg/kg/day);1 for liver
tumors only, and a slope factor of 7.5 x 104 (mg/kg/day)"1 for
pooled significantly increased tumors of the liver, lung or nasal
turbinates/hard palate. The latter method avoids double-counting
of tumor-bearing animals (Bayard, 1990).
The Human Cancer Criterion is based on the pooled
significant tumors in female rats of Kociba et al. (1978) with
the liver tumor reevaluation of the Pathology Working Group
(Sauer, 1990). The linearized multistage model generates a slope
factor of 7.5 x 104 (mg/kg/day)'1 from these data.
RAD = Risk Level = 1 x IP'5
ql* 7.5 x 104 (mg/kg/d)'1
= 1.33 x 10'10 mg/kg/d
Drinking Water Sources:
HNV - RAD x BW
WCd + [(FCTL3 x BAFju) + (PC™ x
- _ 1.33 x IP'10 mq/ka/d x 70 kg _
2 1/d + [(0.0036 x 48,490) + (0.0114 x 79,420)]
= 8.6 x 10'9 ug/L
Non-Drinking Water Sources:
HNV = _ RAD x BW _
WCr + [{FCTL3 x BAFra) + (PC™ x
71
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1.33 x IP'10 ma/ka/d x 70 ka
0.01 1/d + [(0.0036 x 48,490) + (0.0114 x 79,420)]
= 8.6 x 10'9 ug/L
References:
Bayard, S. 1990. Toxicologist/Statistician with the U.S. EPA
Office of Research and Development, Human Health Assessment
Group. Personal communication with R. Sills, Michigan Department
of Natural Resources.
Fingerhut, M. et al. 1991. Cancer mortality in workers exposed
to 2,3,7,8-tetrachlorodibenzo-p-dioxin. The New England Journal
of Medicine. 234(4):212-218.
Goodman, D. and R.M. Sauer. 1992. Hepatoxicity and
carcinogenicity in female Sprague-Dawley rats treated with
2,3,7,8-TCDD: A pathology working group reevaluation. Reg.
Toxicol. Pharamcol. 15:245-253.
Kociba, R.J. et al. 1978. Results of a two-year chronic
toxicity and oncogenicity study of 2,3,7,8- tetrachlorodibenzo-p-
dioxin in rats. Toxicol. Applied Pharmacol. 46:279-303.
National Toxicology Program (NTP). 1982a. Bioassay of
2,3,7,8-tetrachlorodibenzo-p-dioxin in Osborne-Mendel Rats and
B6C3F1 Mice (Gavage Study). NTP-TR-209. National Toxicology
Program, U.S. DHHS, Research Triangle Park, NC.
National Toxicology Program (NTP). 1982b. Carcinogenesis
Bioassay of 2,3,7,8-tetrachlorodibenzo-p-dioxin in Swiss-Webster
Mice (Dermal Study). NTP-TR-201. National Toxicology Program,
U.S. DHHS, Research Triangle Park, NC.
Sauer, R.M. 1990. Pathology Working Group: 2,3,7,8-
Tetrachlorodibenzo-p-dioxin in Sprague-Dawley Rats. Pathco, Inc.
Submitted to the Maine Scientific Advisory Panel.
U.S. Environmental Protection Agency (EPA). 1984. Ambient Water
Quality Criteria4 for 2,3,7,8-Tetrachlorodibenzo-p-dioxin. EPA
440/5-84-007.
Van Miller, J.P. et al. 1977. Increased incidence of neoplasms
in rats exposed to low levels of 2,3,7,8- tetrachlorodibenzo-p-
dioxin. Chemosphere 6(10):625-632.
Zober, A., P. Messerer and P. Huber. 1990. Thirty-four-year
mortality follow-up of BASF employees exposed to 2,3,7,8-TCDD
72
-------
after the 1953 accident. Int. Arch. Occup. Environ. Health.
62(2):139-157.
73
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GREAT LAKES WATER QUALITY INITIATIVE
'TIER i HUMAN HEALTH CRITERIA FOR
TOLUENE
CAS NO. 108-88-3
Tier 1 HtT|nar> Moncancer Criterion
A review of the available literature indicates inadequate
human data for quantitative risk assessment of toluene based on
human health eff.ects. Occupational exposure, cigarette smoking
and deliberate inhalation of solvents found in various
preparations ("glue sniffing") are common means of human exposure
to toluene (NTP, 1990). Chronic exposure to toluene vapors at
levels of approximately 200-800 ppm have been associated
primarily with CNS effects, possibly peripheral nervous system
effects, hepatomegaly and hepatic function changes, and renal
function effects (EPA, 1987). Although these findings provide
qualitative evidence of the human toxicity of toluene, specific
exposure levels were not provided and these data do not provide a
dose-response relationship (EPA, 1987; EPA, 1990; NTP, 1990).
The majority of the subchronic-chronic studies on toluene
are inhalation studies determining behavioral or histopathologic
effects of toluene exposure. The most appropriate basis for HNV
derivation for toluene is the NOAEL from a 13-week rat gavage
study (NTP, 1990). In this study, toluene in corn oil was
administered by gavage to groups of weanling F344/N rats and
B6C3F1 mice (10/sex/group) at dose levels of 0, 312, 625, 1250,
2500 or 5000 mg/kg, 5 days per week for 13 weeks. All rats at
5000 mg/kg died during the first week, and 8/10 rats at 2500
mg/kg died, two of which were due to gavage errors.
Histopathologic changes were observed in the liver, kidney, brain
and urinary bladder at a 1250 mg/kg. The NOAEL for the rats is
312 mg/kg/day with a LOAEL based on liver and kidney weight
changes in male rats at 625 mg/kg. Because the exposure was for
5 days/week, these doses are converted to time-weighted-average
doses of 223 and 446 mg/kg/day, respectively (EPA, 1990) .
As described above, NTP (1990) also conducted a 13-week
gavage study in B6C3F1 mice. All mice that received 5000 mg/kg
died during the first week, and 40% of those that received 2500
mg/kg died before the end of the 13-week gavage study. Clinical
signs observed in mice at 2 2500 mg/kg included sub-convulsive
jerking, prostration, impaired grasping reflex, bradypnea,
hypothermia, hypoactivity and ataxia. The final mean body weight
of males at 2500 mg/kg was lower than that of vehicle controls.
At a 1250 mg/kg, relative liver weights were increased for mice,
but this increase was not statistically significant. The NOAEL
for this study was 1250 mg/kg and the LOAEL was 2500 mg/kg.
Adjusting the doses for 5 days/week exposure provides time-
weighted- average NOAEL and LOAEL doses of 893 and 1786 mg/kg/day,
respectively.
Another subchronic oral toxicity study was conducted by Wolf
et al. (1956), in which female Wistar rats were administered
74
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toluene by stomach tube at doses of 0, 118, 354 and 590
ing/kg/day, 5 days/week for a total of 138 doses (converted to
time-weighted-average doses of approximately 0, 18, 253, and 422
mg/kg/day per EPA, 1990) . No adverse effects were observed at
any dose level in any of the parameters monitored: growth,
appearance and behavior, mortality, organ/body weight, blood urea
nitrogen levels, bone marrow counts, peripheral blood counts or
morphology of major organs. The NOAEL for this study was 422
mg/kg/day as the time-weighted-average dose.
NYLAR mice were exposed pre- and post-natally to toluene
provided in the drinking water at concentrations of 0, 16, 80 and
400 ppm (Kostas and Hotchin, 1981). Rotorod performance was
measured at 45 and 55 days of age. An inverse dose-response
relationship in the effects was noted in which rotorod
performance was improved with increasing dose. No effects were
observed for the following reproductive measurements: maternal
fluid consumption, offspring mortality rate, development of eye
or ear openings,- or surface-righting response, resulting in a
NOAEL of 400 ppm. Assuming mice consume water at appoximately
0.24 I/kg bw/day (EPA, 1988), the NOAEL was approximately 96
mg/kg/day.
Nawrot and Staples (1979) administered 0.3, 0.5 or 1.0 ml/kg
bw toluene, 3 times/day (equivalent to approximately 780, 1300
and 2600 mg/kg/day, per EPA, 1990) to pregnant CD-l mice from
days 6-15 of gestation. No method of exposure was mentioned in
this limited information abstract. Teratogenic effects were
reported at 2600' mg/kg/day and increased embryolethality was
reported at a 780 mg/kg/day, therefore the LOAEL for this study
was 780 mg/kg/day.
No other subchronic-chronic oral toxicity studies were
identified in the available literature for toluene. Chronic
inhalation studies include NTP (1990), in which F344/N rats and
B6C3F1 mice (60/sex/dose) were exposed to vapors of toluene, 6.5
hours/day, 5 days/week for 2 years. Dose levels were 0, 120
(mice only), 600 or 1200 ppm. Ten animals/group (except male
mice) were removed at 15 months for toxicologic evaluation. At
15 months, there was an increased incidence and severity in the
erosion of olfactory epithelium, and degeneration of respiratory
epithelium was increased in the exposed rats. At the end of the
study inflammation of nasal mucosa and metaplasia of olfactory
epithelium were increased in exposed females rats. Nephropathy
was seen in almost all rats with a severity somewhat increased in
exposed rats. For mice, no biologically relevant increase in any
nonneoplastic lesion was observed.
Chronic inhalation of toluene was studied in F344 rats
exposed to 30, 100 or 300 ppm (113, 377 or 1130 mg/m3) toluene 6
hours/day, 5 days/week for 24 months (Gibson and Hardisty, 1983;
CUT, 1980, as cited in NTP, 1990; EPA, 1990; and EPA, 1987). A
dose-related reduction in hematocrit values was reported in
female rats exposed to 100 and 300 ppm. Increased corpuscular
hemoglobin concentration was reported in females at 300 ppm.
75
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In a perinatal study with CD-I mice (Courtney et al., 1986),
toluene was administered by inhalation at 200 and 400 ppm (750
and 1500 mg/m3, respectively) to pregnant female CD-I mice 7
hours/day from days 6-16 of gestation. Fetotoxicity was observed
at 400 ppm with a significant shift in the fetal rib profile. An
increased body weight in the neonates on day 1 postpartum was
observed at 400 ppm. At 200 ppm, there was an increase in
dilated renal pelves which the authors concluded might reflect
desynchronization of maturation with respect to development and
growth. Assuming that mice breathe appoximately 1.7 nr/kg/day
(EPA, 1988) , the 7 hours/day 200 ppm LOAEL and 400 ppm PEL
convert to approximately 370 and 740 mg/kg/day, respectively, as
daily administered doses.
The Tier 1 HNC is derived from the NOAEL dose of 312 mg/kg
(converted to 22-3 mg/kg/day for 5 days/week administration) from
the 13 -week oral rat study by NTP (1990) with an uncertainty
factor of 1000. The uncertainty factor accounts for interspecies
variation, intraspecies differences, and subchronic exposure
duration. This approach should be protective of developmental
effects, as suggested by the limited developmental toxicity data.
This approach is consistent with the risk assessment of toluene
for the oral RfD and the drinking water health advisory developed
by EPA (1990; 1987) .
ADE = 223 ma/ka/d = 2.23 x 10'1 mg/kg/day
1,000
Where: Uncertainty Factor = 1,000, composed of:
lOx for interspecies variability
lOx for intraspecies differences
lOx for subchronic exposure duration
Drinking Water Sources:
HNV = _ APE x BW x RSC _
WCd + [ (FCTu x BAFTu) + (FC^ x
- 2.23 x IP'1 ma/ka/d x 70 kcr x 0.8
2 1/d + [(0.0036 x 11) + (0.0114 x 17)3
= 5.6 x 103 ug/L
Non-Drinking Water Sources:
HNV = _ ADE X BW X RSC _
WCr + [(FCTu x BAF-ru) + (FC^ x BAFTM) ]
2.23 x IP'1 ma/ka/d x 70 ka x 0.8
0.01 1/d. + [(0.0036 x 11) + (0.0114 x 17)]
76
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= 5.1 x 104 ug/L
References:
Chemical Industry Institute of Technology (CUT). 1980. A 24-
Month Inhalation. Toxicology Study in Fischer-344 Rats Exposed to
Atmospheric Toluene. CUT, Research Triangle Park, NC. As cited
in EPA, 1987; EPA, 1990; NTP, 1990.
Courtney, K.D., J.E. Andrews, J. Springer, M. Menache, T.
Williams, L. Dalley and J.A. Graham. 1986. A perinatal study of
toluene in CD-I mice. Fundam. Appl. Toxicol. 6:145-154.
Gibson, J.E. and J.F. Hardisty. 1983. Chronic toxicity and
oncogenicity bioassay of inhaled toluene in Fischer-344 rats.
Fundam. Appl. Toxicol. 3:315-319.
Kostas, J. and J. Hotchin. 1981. Behavioral effects of low-
level perinatal exposure to toluene in mice. Neurobehav.
Toxicol. Teratol. 3:467-469.
National Toxicology Program (NTP). 1990. Toxicology and
Carcinogenesis Studies of Toluene (CAS No. 108-88-3) in F344/N
Rats and B6C3F1 Mice (Inhalation Studies). NTP-TR. No. 371, NIH
Publication No. 90-2826.
Nawrot, P.S. and R.E. Staples. 1979. Embryo-fetal toxicity and
teratogenicity of benzene and toluene in the mouse. Teratology.
19:41A (abstract).
U.S. Environmental Protection Agency (EPA). 1990. Integrated
Risk Information System (IRIS database). Chemical file for
toluene (108-88-3). Verification Date 6/20/90. Last Reviewed
6/20/90.
U.S. Environmental Protection Agency (EPA). 1988.
Recommendations for and Documentation of Biological Values for
Use in Risk Assessment. PB88-179874.
U.S. Environmental Protection Agency (EPA). 1987. Drinking
Water Criteria Document for Toluene. Prepared by the Office of
Health and Environmental Assessment, Environmental Criteria and
Assessment Office, Cincinnati, OH for the Office of Drinking
Water, Washington, DC. ECAO-CIN-408.
Wolf, M.A., V.K. Rowe, D.D. McCollister, R.L. Hollingsworth and
F. Oyen. 1956. Toxicological studies of certain alkylated
benzenes and benzene. A.M.A. Arch. Ind. Health. 14:387-398.
Tier 1 Human Cancer Criterion
Toulene is not considered carcinogenic.
77
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GREAT LAKES WATER QUALITY INITIATIVE
TIER 1 HUMAN HEALTH CRITERIA FOR
TOZAPHENE
CAS NO. 8001-35-2
ir Criterion
EPA is currently reviewing the RfD for toxaphene. Because
there is no EPA verified RfD that can be used for derivation of a
Tier I human noncancer, the final Guidance does include a
noncancer criterion for toxaphene.
Tier i TTntnan Canc6ir Criterion
According to EPA (1985; 1987), there are inadequate data
available to ascertain whether toxaphene is a human carcinogen.
However, two chronic studies have shown that toxaphene induces
the formation of liver tumors in B6C3F1 mice. One of these
studies also found that toxaphene induces the formation of
thyroid tumors in Osborne- Mendel rats. Toxaphene was mutagenic
for Salmonella typhimurium strains TA98 and TA100 (Hill, 1977 as
cited by EPA, 1985) and was also found to induce the formation of
sister chromatid exchanges in Chinese hamster lung (DON) cells
(Steinel et al., 1990). However, toxaphene produced a negative
response in a modified dominant lethal assay which used male
ICR/Ha Swiss mice (Epstein et al., 1972). According to EPA
(1985; 1987) , the weight -of -evidence for toxaphene
car cinogeni city is sufficient for B2 classification (probable
human carcinogen) . The data are sufficient to derive a Tier 1
HCC.
In a study conducted by NCI (1979) , 50 Osborne -Mendel
rats/sex/group and 50 B6C3F1 mice/sex/group were administered
toxaphene in their diets for 80 weeks. Male rats received time-
weighted average (TWA) doses of 112 and 556 ppm, while females
received TWA doses of 540 and 1080 ppm. Both male and female
mice received TWA doses of 99 and 198 ppm. Both rats and mice
had 10 matched controls/sex with an additional 45 pooled
controls/sex for rats and 40 additional pooled controls/sex for
mice. Male and female rats exhibited a statistically significant
dose -related increased incidence of thyroid tumors (adenomas and
carcinomas) , whereas treated mice exhibited a statistically
significant dose- related increased incidence of liver tumors
(NCI, 1979).
In a study conducted by Litton Bionetics (1978, as cited by
EPA, 1987) , toxaphene was administered to B6C3F1 mice (54
mice/sex/group) in the diet for 18 months at doses of 0, 7, 20
and 50 ppm. Animals were observed for a period of 6 months after
treatment. An increased incidence of hepatocellular tumors
(adenomas and carcinomas) was seen in both sexes and was
statistically significant in males administered 50 ppm. This
78
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study, rather than the NCI study, was used for cancer risk
assessment because it utilized more dose levels and a lower range
of doses while still eliciting a tumorigenic response in the
liver. EPA (1987) recommends the same key study and slope factor
(1.1 (mg/kg/d)"1) as utilized for HCC derivation.
RAD = Risk Level - 1 x IP'5
ql* l.l (mg/kg/d)-1
= 9.09 x KT6 mg/kg/d
Drinking Water Sources:
HNV = _ RAD x BW _
WCd + [ (FCTL3 X BAF^) + (FC™ x
- _ 9.09 x 1Q-6 ma/ka/d x 70 ka _
2 1/d + [(0.0036 x 498,100) + (0.0114 x 665,600)]
= 6.8 x 10;5 ug/L
Non-Drinking Water Sources:
HNV = _ RAD x BW
WCr + [(FCnj x BAFro) + (FC^ X
= _ 9.09 x IP"* ma/ka/d x 70 ka _
0.01 1/d + [(0.0036 x 498,100) + (0.0114 x 665,600)]
= 6.8 x 10'5 ug/L
References :
Epstein, S.S., E. Arnold, J. Andrea, W. Bass and Y. Bishop.
1972. Detection of chemical mutagens by the dominant lethal assay
in the mouse. Toxicol. Appl. Pharmacol. 23:288-325.
Hill, R.N. 1977-. Memorandum to Fred Hagemen. Off. Spec.
Pestic. Rev., U.S. EPA. December 15. As cited in: EPA, 1984.
Litton Bionetics. 1978. Carcinogenic evaluation in mice:
Toxaphene. Prepared by Litton Bionetics, Inc., Kensington, MD
for Hercules, Inc., Wilmington, DE.
National Cancer Institute (NCI). 1979. Bioassay of Toxaphene
for Possible Carcinogenicity. Carcinogenesis Testing Program.
Division of Cancer Cause and Prevention. NCI, National Institute
of Health, Bethesda, Maryland, 20014. U.S. Department of
Health, Education and Welfare. DHEW Publication No. (NIH) 79-
837.
79
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Steinel, H.H., A. Arlauskas and R. S. Baker. 1990. SCE
induction and cell-cycle delay by toxaphene. Mutat. Res.
230:29-33.
U.S. Environmental Protection Agency (EPA). 1985. Drinking
Water Criteria Document for Toxaphene. Environmental Criteria
and Assessment Office. Cincinnati, OH. PB 86-118049.
U.S. Environmental Protection Agency (EPA). 1987. Integrated
Risk Information System (IRIS database). Chemical file for
toxaphene (8001-35-2). Verification Date 3/5/87. Last Revised
1/1/91.
80
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GREAT LAKES WATER QUALITY INITIATIVE
TIER 1 HUMAN HEALTH CRITERIA FOR
TRICHLOROETHYLENE
CAS NO. 79-01-6
Tier T H»mmr» Noncancez" Criterion
EPA is currently reviewing the RfD for trichloroethylene.
Because there is no EPA verified RfD that can be used for
derivation of a Tier I human noncancer, the final Guidance does
include a noncancer criterion for trichloroethylene.
Six epidemiologic studies have been performed to investigate
the carcinogenicity of trichloroethylene (TCE) in exposed workers
(Axelson et al., 1978; Hardell et al.f 1981; Malek et al., 1979;
Novotna et al., 1979; Paddle, 1983; Tola et al, 1980). Results
of those studies were inadequate to attribute cancer incidence to
TCE exposure. However, because they suffer from various
limitations and deficiencies, they also fail to provide adequate
evidence that TCE is not a human carcinogen (EPA, 1985).
Based on weight of evidence, EPA (1985, 1987, 1988)
classified TCE in Group B2- Probable Human Carcinogen. The
evidence reviewed by EPA (1985) for carcinogenicity of TCE in
experimental animals includes increased incidence of
hepatocellular carcinomas in male and female B6C3F1 mice (NCI,
1976; NTP, 1982, 1986) by gavage, malignant lymphomas in female
HanrNMRI mice by inhalation (Henschler et al., 1980); and renal
adenocarcinomas in male Fischer 344 rats by gavage (NTP, 1982,
1986). Evidenre presented in EPA (1987) markedly strengthened
the B2 classification by showing that inhalation is a second
exposure route that results in carcinogenic activity in rats and
mice, and by identifying diverse tumor sites (EPA, 1987).
EPA (1985) developed a quantitative cancer risk assessment
based on four sets of gavage bioassay data that show
hepatocellular carcinomas in male and female mice {NTP, 1982;
NCI, 1976). The NCI bioassay involved exposure by gavage to
B6C3F1 mice. Although rats were also tested, excessive mortality
in all groups cast doubt on the adequacy of those results. Mice
were dosed in groups of 50 animals per sex, 5 days/week for 78
weeks. Surviving animals were sacrificed at 90 weeks and
subjected to complete necropsy and histopathological examination.
The time-weighted-average (TWA) doses for male mice were 1,169
and 2,339 mg/kg, and for the female mice they were 869 and 1,739
mg/kg. The study included 20 matched vehicle control animals of
each sex. It was concluded that TCE induced a statistically
significant (p < 0.05) increase in the incidence of
hepatocellular carcinoma in both male and female B6C3F1 mice. A
reduction in the time-to-tumor response was also reported among
male mice at the high dose level. The presence of the trace
contaminant epichlorohydrin (0.09%) in the test material for this
81
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bioassay could be a cause for concern. However, it has been
determined that any potential contribution of epichlorohydrin to
the overall carcinogenic potency of TCE in the bioassay was
negligible (EPA/ 1985).
NTP (1982) conducted a carcinogenicity bioassay on TCE in B6C3F1
mice and F344/N rats. The rats experienced reduced survival when
compared to controls, and the results were therefore invalidated.
Male and female mice were dosed by gavage at 1,000 mg/kg, 5
days/week for 103 weeks. Survival was significantly lower (p <
0.004) in treated males whereas survival in treated females was
lower after 95 weeks, but the overall difference between vehicle
controls and treated females was not significant. Male and
female mice had a statistically significant increase in the
incidence of hepatocellular carcinoma (p <. 0.002) and
hepatocellular adenoma (p < 0.05) over corresponding vehicle
controls. The TCE test material for that bioassay was not
contaminated with detectable amounts of epichlorohydrin. The
potency of TCE with regard to the induction of hepatocellular
carcinomas in mice has been determined to be very similar in the
NTP (1982) bioassay and the NCI (1976) bioassay (EPA, 1985).
Additional studies were reviewed by EPA (1987) identifying
positive findings by inhalation exposure in rats and mice.
Maltoni et al. (1986) conducted bioassays of Sprague-Dawley rats
exposed to 0, 100, 300 and 600 ppm of TCE 7 hours/day, 5
days/week for 104 weeks. Necropsy was performed on all animals.
Male rats demonstrated increased incidence of renal tubuli
megalonucleocytosis and renal adenocarcinomas, and a slight
increase in leukemias, particularly immunoblastic lymphosarcomas.
Maltoni et al. (1986) also conducted bioassays on Swiss mice and
B6C3F1 mice (90 mice/strain/sex/group) exposed to 0, 100, 300,
and 600 ppm TCE for 78 weeks. Statistically significant
increases in hepatomas were noted among male Swiss mice at the
high concentration, and significant increases in pulmonary tumors
were observed among male Swiss mice at high and medium exposures.
Among the B6C3F1 mice, there were increases in hepatomas in males
and females, pulmonary tumors in females, and in the total number
of tumors among females at all concentrations.
Fukuda et al., (1983) reported the results of bioassays with
female ICR mice and Sprague-Dawley rats (49-50 per group) exposed
to airborne concentrations of 0, 50, 150, and 450 ppm of TCE for
7 hours/day, 5 days/week for 107 weeks. There were no
statistically significant increases in tumors among rats, however
a statistically significant increase in lung adenocarcinomas was
found among the mice.
Using the mice liver tumor data sets from NTP (1982) and NCI
(1976), EPA (1985) calculated human slope estimates of 1.9 xlO'2,
8.0 x 10'3, 1.8 x-10'2, and 5.8 x 10'3 (mg/kg/day)"1. Because the
slope estimates from these four data sets were found to be
comparable, their geometric mean was used to derive the
recommended slope factor of 1.1 x 10"2 (mg/kg/day)'1. EPA (1987)
82
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also developed slope factors from the inhalation studies of
Maltoni et al. (1986) and Fukuda et al.(1983). These slope
factors were found to be comparable to the qj* developed earlier
from the gavage studies (EPA, 1987).
EPA is currently reviewing the carcinogenicity data for
trichloroethylene. Based on this review EPA may change the
carcinogenicity characterization for trichloroethylene. However,
until this review is completed the previously verified oral slope
factor of 1.1 x -lO'2 (mg/kg/day)-1 will be used.
RAD - Risk Level - 1 x IP'5
ql* 1.1 x 1CT2 (mg/kg/d)'1
= 9.09 x 1CT4 mg/kg/d
Drinking Water Sources:
HNV = ; RAD x BW
WCd + [(FCTL3 x BAFTLJ) + (FCn, x
= _ 9.09 x 1CT* mcr/ka/d x 70 ka
2 1/d + [(0.0036 x 7) + (0.0114 x 12)]
= 29 ug/L
Non-Drinking Water Sources:
HNV = _ RAD x BW _
WCr + [(F^ x BAFTu) + (FC™ x
= _ 9.09 x 10^ ma/ko/d x 70 ka _
0.01 1/d + [(0.0036 x 7) + (0.0114 x 12)]
- 3.7 x 102 ug/L
References :
Axelson, 0. et al . 1978. A cohort study on trichloroethylene
exposure and cancer mortality. J. Occup. Med. 20:194-196.
Fukuda, K., K. Takemoto, H. Tsuruta. 1983. Inhalation
carcinogenicity of trichloroethylene in mice and rats. Ind.
Health 21:243-254.
Hardell, L., et al. 1981. Malignant lymphomas and exposure to
chemicals, especially organic solvents, chlorophenols, and
phenoxy acids: a case-control study. Br. J. Cancer. 43:169-176.
Henshler, L. et al. 1980. Carcinogenicity study of
trichloroethylene by long-term inhalation in the animal species.
Arch. Toxicol. 43:237-248.
83
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Malek, B., B. Kromarova, and 0. Rodova. 1979. An
epidemiological study of hepatic tumor incidence in subjects
working with trichloroethylene. II. Negative results of
retrospective investigations in dry-cleaners. Prakov. Lek. 31:
124-126. As cited in EPA (1985).
Maltoni, C., G. Lefemine, and C. Cotti. 1986. Experimental
research on trichloroethylene carcinogenesis. In: Maltoni, C. M.
Melham eds. Archives of Research on Industrial Carcinogenesis.
Vol. V. Princeton NJ. Princeton Scientific Publishing Co.
National Cancer Institute (NCI). 1976. Carcinogenesis Bioassay
of Trichloroethylene. CAS No. 79-01-6. NCI-CG-TR-2.
National Toxicology Program (NTP). 1982. Carcinogenesis Bioassay
of Trichloroethylene. Cas No 79-01-6. NTP 81-84. NIH
Publication No. 82-1799.
National Toxicology Program (NTP). 1986. Toxicology and
Carcinogenesis Studies of Trichloroethylene in F344/N Rats and
B6C3F1 Mice. NTP TR 243. U.S. Department of Health and Human
Services. National Institutes of Health. Bethesda, MD.
Novotna, E., A. David, and B. Malek. 1979. An epidemiological
study on hepatic tumor incidence in subjects working with
trichloroethylene: I. Negative results of retrospective
investigations in subjects with primary liver carcinoma.
Pracovni Lekartsvi. 31(4): 121-123. As cited in EPA (1985).
Paddle, G. 1983. Incidence of liver cancer and
trichloroethylene manufacture: joint study by industry and cancer
registry. British Medical Journal. 286:846.
Tola, S., R. Vilhnuer, E. Jaruinene, and M. Korkale. 1980. A
cohort study of workers exposed to trichloroethylene. J. Occup.
Med. 22:737-740.
U.S. Environmental Protection Agency (EPA). 1988. Health Effects
Assessment for Trichloroethylene. EPA/600/8-89/097. Washington,
D.C.
U.S. Environmental Protection Agency (EPA). 1987. Addendum to
the Health Assessment Document for Trichloroethylene: Updated
Carcinogenicity Assessment for Trichloroethylene. EPA/600/8-
82/006. Washington, D.C.
U.S. Environmental Protection Agency (EPA). 1985. Health
Assessment Document for Trichloroethylene. EPA/600/8-82/006F
Washington, D.C.
84 U.S. Environmental Protection Agency
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