United States Prevention, Pesticides EPA712-C-96-261
Environmental Protection and Toxic Substances February 1996
Agency (7101)
&EPA Occupational and
Residential Exposure
Test Guidelines
OPPTS 875.1000
Background for
Application Exposure
Monitoring Test
Guidelines
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INTRODUCTION
This guideline is one of a series of test guidelines that have been
developed by the Office of Prevention, Pesticides and Toxic Substances,
United States Environmental Protection Agency for use in the testing of
pesticides and toxic substances, and the development of test data that must
be submitted to the Agency for review under Federal regulations.
The Office of Prevention, Pesticides and Toxic Substances (OPPTS)
has developed this guideline through a process of harmonization that
blended the testing guidance and requirements that existed in the Office
of Pollution Prevention and Toxics (OPPT) and appeared in Title 40,
Chapter I, Subchapter R of the Code of Federal Regulations (CFR), the
Office of Pesticide Programs (OPP) which appeared in publications of the
National Technical Information Service (NTIS) and the guidelines pub-
lished by the Organization for Economic Cooperation and Development
(OECD).
The purpose of harmonizing these guidelines into a single set of
OPPTS guidelines is to minimize variations among the testing procedures
that must be performed to meet the data requirements of the U. S. Environ-
mental Protection Agency under the Toxic Substances Control Act (15
U.S.C. 2601) and the Federal Insecticide, Fungicide and Rodenticide Act
(7U.S.C. I36,etseq.).
Final Guideline Release: This guideline is available from the U.S.
Government Printing Office, Washington, DC 20402 on The Federal Bul-
letin Board. By modem dial 202-512-1387, telnet and ftp:
fedbbs.access.gpo.gov (IP 162.140.64.19), internet: http://
fedbbs.access.gpo.gov, or call 202-512-0132 for disks or paper copies.
This guideline is also available electronically in ASCII and PDF (portable
document format) from the EPA Public Access Gopher (gopher.epa.gov)
under the heading "Environmental Test Methods and Guidelines."
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OPPTS 875.1000 Background for application exposure monitoring
test guidelines.
(a) Scope—(1) Applicability. This guideline is intended to meet test-
ing requirements of the Federal Insecticide, Fungicide, and Rodenticide
Act (FIFRA) (7 U.S.C. 136, et seq.}.
(2) Background. The source material used in developing this har-
monized OPPTS test guideline is OPP guideline 230.
(b) FIFRA and applicator exposure—a regulatory overview. The
increasing concern over pesticides in the environment during the 1960's
caused a shift in the thrust of pesticide regulation from one of efficacy
(protection of pesticide users from fraudulent product claims) to one of
protection of the environment and public health. The legislative basis for
the regulation of pesticides is the Federal Insecticide, Fungicide, and
Rodenticide Act (FIFRA). This Act was amended significantly in 1972
with the creation of a criterion set forth to prevent ' 'unreasonable adverse
effects on the environment." This is defined as "any unreasonable risk
to man or the environment, taking into account the economic, social and
environmental costs and benefits of the use of any pesticide." Amend-
ments to FIFRA in 1975, 1978, 1988, and 1980 have not altered this basic
risk criterion for regulatory decision making.
(1) Scientists in the Occupational and Resident Exposure Branch
(OREB) of the Health Effects Division (HED) of OPP have the respon-
sibility for estimating actual worker exposure. Agricultural scientists in
OPP's Benefits and Economic Analysis Division (BEAD) supply pertinent
use information along with estimates of the frequency and duration of each
application activity for which an exposure assessment is prepared. The es-
timated exposure for the required time interval (daily or annually depend-
ing on whether the assessment is for an acute or chronic toxicological
concern) is given to HED's Toxicology Branch (TB), where it is consid-
ered along with the results of the biological effects studies to produce
a quantitative risk assessment. The risk assessment is considered in the
risk/benefit analysis required for regulatory decisions under FIFRA.
(2) To implement the 1972 amendments to FIFRA, the Agency devel-
oped the Rebuttable Presumption Against Registration (RPAR) process and
published the criteria which trigger the detailed determination of unreason-
able adverse effects associated with a given pesticide use under paragraph
(h)(22) of this guideline. At the onset of the RPAR process it was apparent
that the risks to individuals who apply pesticides are distinct from those
to the general population, and must be considered under the broad um-
brella of the unreasonable adverse effects criterion under paragraphs
(h)(23), (h)(24), (h)(25), and (h)(26) of this guideline.
(3) It became apparent during the early RPARs that few data were
available for estimating the occupational exposure of pesticide applicators
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and mixer/loaders. The components of a quantitative risk assessment are
hazard assessment, usually a study of the toxicological response of labora-
tory animals to a chemical, and exposure. Occupational exposure could
not generally be estimated with any certainty. A committee of the National
Research Council (NRC), commissioned with the task of analyzing the
effectiveness of the RPAR process, noted under paragraph (h)(66) of this
guideline:
In estimating exposure, as in other phases of its work, OPP is constantly
hampered by lack of adequate data, and is forced to resort to indirect and inac-
curate methods in its effort to make plausible estimates.
(4) A 1978 amendment to FIFRA emphasized the importance of accu-
rately evaluating exposure in OPP's regulatory decisions. Section 3(c)(8)
was added to FIFRA and states (in part):
Notwithstanding any other provision of this Act, the Administrator may not
initiate a public interim administrative review process to develop a risk-benefit
evaluation of the ingredients of a pesticide or any of its uses prior to initiating
a formal action to cancel, suspend, or deny registration of such a pesticide, re-
quired under this Act, unless such interim administrative process is based on
a validated test or other significant evidence raising prudent concerns of unrea-
sonable adverse risk to man or the environment.
(5) While "exposure" does not appear in this section of FIFRA, this
is clearly what Congress intended with the phrase "prudent concerns of
unreasonable adverse risk." The House-Senate Conference Report discuss-
ing this section of the 1978 amendments under paragraph (h)(9) of this
guideline states:
Human exposure to pesticides through any medium or pathway is a central
issue in evaluating the unreasonable adverse effects of pesticide products. Where
this issue can be resolved without an RPAR being initiated, it shall be.
(6) In discussing the amendments, Rep. Foley stated under paragraph
(h)(10) of this guideline:
To avoid the time consuming RPAR process, the Administrator is directed
to establish suitable scientific protocols for development of human exposure data
. . . and then to evaluate and weigh such data prior to initiating an RPAR process.
(7) The RPAR triggers promulgated in 1975 were based solely on
toxicological hazards and did not take exposure into account. These trig-
gers have now been replaced by new criteria initiating the assessment of
unreasonable adverse effects which do consider the likely level of expo-
sure. The RPAR process is now called the "Special Review" process
under paragraph (h)(30) of this guideline.
(8) A consequence of the 1978 amendments to FIFRA is that applica-
tor risk assessments, traditionally done only for registered pesticides under
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RPAR review, must now be undertaken for pesticides undergoing registra-
tion or reregistration (Registration Standard) review as well as Special Re-
view, when a potential toxicological concern has been identified.
(9) While the unreasonable adverse effects criterion of FIFRA does
not make a distinction between indoor and outdoor uses of pesticides, his-
torically most regulatory attention has been focused on the outdoor uses
of pesticides under paragraph (h)(75) of this guideline. The review of
many of the older, persistent pesticides used on food crops has been very
resource-intensive and has lessened the Agency's ability to address concur-
rently the indoor uses. With the recent increased concern for human health
and the indoor environment under paragraph (h)(84) of this guideline, ac-
tivity in the areas of monitoring and evaluating the indoor uses of pesticide
chemicals has increased.
(10) Consequently, these guidelines will cover exposure monitoring
studies for both outdoor and indoor sites. For many indoor uses, the indi-
vidual who applies the pesticide also works or resides in the building.
As stated in the previous section, indoor exposure to pesticides is not cur-
rently addressed in other subdivisions of these guidelines. Accordingly,
both application and ambient exposure will be addressed for indoor uses.
(11) Individuals who have contact with pesticides in the course of
their work activities will be exposed to these chemicals through different
routes and to a different extent than the general population. The purpose
of OPPTS guidelines 875.1100 through 875.1700 is to aid pesticide reg-
istrants and others in designing and carrying out field studies which meas-
ure, using personal monitoring techniques, potential dermal and respiratory
exposure to pesticides when used according to widespread and commonly
recognized practice. These guidelines address direct exposure encountered
during any pesticide application operation and related occupational activi-
ties including weighing and mixing the concentrated chemical, loading the
material into the application equipment, etc. These guidelines also include
indoor testing procedures to measure postapplication exposure to persons
as a result of indoor use of pesticides.
(c) Monitoring exposure using passive dosimetry and biological
monitoring—(1) Definitions, (i) Passive dosimetry estimates the amount
of a chemical impinging on the surface of the skin or the amount of the
chemical available for inhalation through the use of appropriate trapping
devices.
(ii) Biological monitoring estimates internal dose from either a meas-
urement of body burden in selected tissues or fluids or from the amount
of pesticide or its metabolites eliminated from the body.
(2) Theoretical and practical advantages and disadvantages of
both approaches—(i) Passive dosimetry. Traditionally, applicator expo-
sure monitoring studies carried out for the Agency have employed passive
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dosimetry techniques. Because of this history of use, experimental design
and execution of exposure studies by passive dosimetry are routine for
many investigators.
(A) The major advantages of direct entrapment procedures are the
ability to differentiate exposure received during discrete work activities
within a work day and in differentiating the relative contributions of the
dermal and respiratory exposure routes for each separate work
activityunder paragraph (h)(20) of this guideline. These advantages are ex-
tremely important for evaluating exposure reduction safety practices such
as personal protective equipment for the various work activities associated
with pesticide application. For example, if a substantial fraction of total
exposure for a work day occurs to the hands, forearms, and face during
the short period of time a worker pours a concentrated pesticide formula-
tion into a mix tank, risk may be mitigated significantly by requiring
chemical resistant gloves, a face shield, and/or a closed mixing system
for this short duration/high exposure period. Since passive dosimetry meas-
ures only the amount of chemical potentially available for absorption, inde-
pendent estimates of dermal and lung absorption are required to estimate
dosage for hazard assessment purposes. These absorption estimates are
generally difficult to derive and interpret using data available from either
in vivo or in vitro penetration studies. In addition, when using passive
dosimetry, assumptions concerning the value of the clothing worn on the
interception of pesticide residues must also be made.
(B) A potential source of error in the use of patches for sample collec-
tion is the extrapolation from the residues on the relatively small surface
area of the trapping devices to entire body surface areas. Also, when using
the patch technique, crucial areas of exposure may be missed depending
on the location of the trapping devices under paragraph (h)(34) of this
guideline. A unique advantage of passive dosimetry is the ability to create
large generic data bases from studies carried out with different pesticides.
The use of the generic approach is discussed in detail in paragraph (f)
of this guideline. Another advantage in using passive dosimetry is that
the study participants are typically under the supervision of the investigator
during the entire period when exposure data are being collected. A more
detailed description of the methods used in passive dosimetry is contained
in paragraph (e) of this guideline.
(ii) Biological monitoring. (A) The distinct theoretical advantage of
the biological monitoring approach is that, under proper conditions, actual
dose may be estimated from the results of the monitoring study. Biological
monitoring implies that a biological measurement is intrinsic to the experi-
mental design of an exposure assessment study. The use of the information
derived from biological monitoring studies varies, from the early detection
of a health effect to establishing a correlation between concentration of
a chemical in fluids to absorbed dose.
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(B) An example of the application of biological monitoring to the
detection of a health effect is the analysis of cholinesterase levels in blood
as an indicator or worker exposure to organophosphate pesticides under
paragraph (h)(69) of this guideline. In this approach, medical surveillance
of workers allows the expedient implementation of preventive measures,
as dictated by blood cholinesterase inhibition levels under paragraphs
(h)(46) and (h)(74) of this guideline. A quantification of exposure from
cholinesterase inhibition is not a goal in this situation. Attempts to cor-
relate levels of cholinesterase inhibition with concentrations of parent pes-
ticides or their metabolites in either blood or urine have not been success-
ful (under paragraphs (h)(5), (h)(19), and (h)(77) of this guideline). A
major contributor to this failure is the wide variability of cholinesterase
levels among individuals (see paragraph (h)(72) of this guideline. In its
current practice, this type of medical surveillance is carried out by estimat-
ing a baseline, preexposure level for each worker and an arbitrary inhibi-
tion level is set at which the worker is removed from further exposure.
(C) Correlations between levels of exposure and concentrations of
metabolites in blood have been documented for some industrial chemicals.
The parameter monitored in this case is the formation of covalent adducts
between the chemical, or a metabolite, and hemoglobin. (See paragraphs
(h)(87) and (h)(70) of this guideline.) Examples reported in the literature
where this technique has been applied include ethylene oxide under para-
graph (h)(6) of this guideline, chloroform under paragraph (h)(70) of this
guideline, and aniline under paragraph (h)(67) of this guideline. The route
of exposure in these cases was predominantly inhalation.
(D) The basis for this approach is the ability of the chemical to alkyl-
ate hemoglobin. The reaction may take place directly as with ethylene
oxide or may require metabolic activation to a reactive species as reported
for chloroform and aniline. The selection of hemoglobin as an internal
dosimeter is based on several features:
(7) Hemoglobin contains nucleophilic groups, histidine and cysteine,
thus maximizing trapping efficiency.
(2) Hemoglobin is readily available in large amounts.
(3) The life span of hemoglobin, and its adducts, is about 18 weeks
in humans, providing a stable marker for monitoring work environments
which could be particularly useful for situations involving low-level chron-
ic exposure.
(E) The reaction rate constants for the alkylation reaction of
electrophiles with hemoglobin can be determined in vitro and may be used
in conjunction with the adduct concentration to estimate the in vivo dose.
At this time, this type of analysis has been fully documented in humans
only in the case of exposure to ethylene oxide. For a group of workers
handling ethylene oxide sterilizers, a correlation was established between
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external exposure dose and the amount of covalent adduct formed per gram
of hemoglobinunder paragraph (h)(6) of this guideline.
(F) A different approach, which does not require the intermediacy
of reactive species, involves the measurement of concentrations or parent
chemical(s) and/or corresponding metabolites in urine under paragraph
(h)(l) and (2) of this guideline. Empirical correlations have been devel-
oped for some industrial chemicals which allow estimation of the exposure
based on the rate of urinary excretion of selected markers. Through the
application of biological monitoring to industrial settings, it has become
possible to identify workers at high risk and proceed to modify the oper-
ations or conditions leading to an undesirable high exposure.
(G) For pesticides, urinary metabolites have been used to detect expo-
sure during field operations: Swan, under paragraph (h)(86) of this guide-
line measured paraquat in the urine of applicators; Gollop and Glass, under
paragraph (h)(41) of this guideline, and Wagner and Weswig, under para-
graph (h)(89) of this guideline, measured arsenic in timber applicators;
Lieben et al., under paragraph (h)(57) of this guideline, and Durham and
Wolfe, under paragraph (h)(20) of this guideline, measured /7-nitrophenol
in urine after parathion exposure. A chlorobenzilate metabolite was de-
tected in citrus workers (Levy et al., under paragraph (h)(55) of this guide-
line); phenoxy acid herbicide metabolites in farmers, (Kolmodin-Hedman
et al., under paragraph (h)(49) of this guideline); and organophosphate
metabolites in the urine of people exposed to mosquito treatments (Kutz
and Strassman, under paragraph (h)(50) of this guideline). Davies et al.,
under paragraph (h)(12) of this guideline, used urine metabolites of
organophosphates and carbamates to confirm poisoning cases. These stud-
ies documented exposure, but no quantification of exposure was typically
made from urinary metabolites alone.
(H) Because applicators are often exposed to the same pesticide nu-
merous times over a growing season, proper interpretation of urine data
is difficult unless the pesticide is excreted fairly rapidly or multiple dosing
and overlapping excretion patterns are well understood. Some experiments
have contributed to understanding these problems and illustrate typical dif-
ferences in the rate of absorption and excretion of various pesticides.
Drevenkar et al., under paragraph (h)(18) of this guideline, studied the
excretion of phosalone metabolites in one volunteer. Excretion reached a
peak in 4-5 h, and was not complete in 24 h. Funckes et al., under para-
graph (h)(39) of this guideline, exposed the hand and forearm of human
volunteers to 2 percent parathion dust. During the exposure the volunteers
breathed pure air and placed their forearm and hand into a plastic bag
which contained the parathion. The exposure took place for 2 h and at
various temperatures. There was increased excretion of /7-nitrophenol with
increasing temperature. More importantly, /7-nitrophenol could be detected
in the urine 40 h later.
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(I) In another human experiment, Kolmodin-Hedman et al, under
paragraph (h)(48) of this guideline, applied methylchlorophenoxyacetic
acid (MCPA) to the thigh. MCPA appeared in the urine for 5 days with
a maximum concentration in about 48 h. When administered orally, MCPA
peaked in urine in 1 h and about 40 percent of the dose was excreted
in 24 h.
(J) Seven different organophosphates were fed to rats at two doses
for 3 days. The rats were removed from exposure after the 3rd day, and
urine was collected for the next 10 days (Bradway et al., under paragraph
(h)(5) of this guideline). The percent of the total dose excreted in urine
over 10 days averaged (high and low doses): Dimethoate 15 percent;
dichlorvos 10 percent; ronnel 11 percent; dichlofenthion 57 percent;
carbophenothion 67 percent; parathion 41 percent; and leptophos 52 per-
cent. Very little of this excretion occurred beyond the 3rd day after expo-
sure.
(K) In another experiment, rats were dosed dermally and
intramuscularly with azinphosmethyl (Franklin et al., under paragraph
(h)(36) of this guideline). About 78 percent of the dermal dose had been
excreted in urine in 24 h. For the intramuscular dose the rate of excretion
peaked in 8-16 h, continued at about the same rate for 16 h and declined
to a steady level in 48 h. There was a linear relationship between dose
and urinary excretions.
(L) While biological monitoring theoretically offers a distinct advan-
tage, there are inherent difficulties in study design, execution, and data
interpretation. Prior to establishing specific testing procedures, the experi-
menter must have a broad knowledge of the chemical being tested. The
pharmacokinetics of the chemical of interest must be known and fully un-
derstood so that the appropriate tissue, fluid, or excretion pathway, as well
as the appropriate time periods for monitoring, can be chosen with regard
to this information. Because this level of detailed information is currently
unavailable for many pesticides, extrapolations back to the actual dose are
difficult.
(M) When measuring exposure via a human substrate one must con-
sider the different ways through which a substance may be eliminated
(sweat, urine, saliva, etc.) or that it may be stored in adipose and other
tissues. Because the measurements relevant to the estimation of workers'
exposure to pesticides must be carried out under field conditions, the
Agency believes that urine analysis is a realistic and practical approach
to implement biological monitoring. This emphasis on a particular method
is based on a consideration of the type of information desired and what
is feasible to obtain under field conditions. It should be understood, how-
ever, that this observation is not intended to exclude other methods which
are demonstrably effective.
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(N) Biological monitoring clearly lacks the definition of source of
exposure provided by the passive dosimetry method. The results of an ap-
propriate biological monitoring study provide an integrated exposure pic-
ture. Biological monitoring should be considered a chemical-specific ap-
proach. The potential for extrapolating results of an exposure study to
other pesticides appears limited by probable differences in absorption, me-
tabolism and excretion profiles. Thus the opportunity for developing ge-
neric data bases, such as those from passive dosimetry studies, does not
appear promising. This difficulty, however, may be overcome by the appli-
cation of structure activity principles which would allow the grouping of
pesticides according to chemical descriptors, thus providing a reasonable
foundation for a useful, predictive data base.
(O) A potential difficulty that may be encountered when using a bio-
logical method is obtaining strict cooperation and adherence to protocols
from study participants when collecting samples (urine, saliva, etc.). Mone-
tary incentives are sometimes needed to increase cooperation. This may
be true particularly when monitoring requires invasive collection tech-
niques such as blood sampling. Invasive techniques could also raise legal
and medial questions associated with the field collection of human tissues
and fluids.
(P) A plan for intensive study oversight is necessary to ensure partici-
pant compliance in collection, storage and handling of urine samples in-
cluding before, during, and after exposure to pesticides. It is not always
practical, however, since investigators are usually on site during the work
activities only, while exposure data are collected beyond the supervised
period.
(Q) When a registrant believes that the problems associated with bio-
logical monitoring as described in this section can be overcome for a par-
ticular pesticide and chooses to monitor worker exposure using biological
monitoring, the Agency will carefully evaluate the results and, if judged
valid, use the results in the risk assessment process. In these circumstances,
the theoretical advantage of biological monitoring discussed earlier in this
section would naturally dictate the use of such data. Prior to initiating
a biological monitoring study, however, the registrant must receive Agency
approval of the study protocol.
(R) An examination of the limitations of the trapping devices pres-
ently used in passive dosimetry has suggested exposure scenarios where
it could be necessary to utilize biological monitoring to estimate exposure.
Examples of specific situations not amenable to current passive dosimetry
methodologies include measuring exposure to pesticides in swimming
pools, in dishwashing detergents, or measuring dermal exposure to volatile
organic chemicals. The perceived advantages and disadvantages of passive
dosimetry and biological monitoring are summarized in the following
Table 1. The observations listed in Table 1. may be considered as initial
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guidance in determining the feasibility of conducting an exposure study
by either method.
Table 1.—The Perceived Advantages and Disadvantages of Estimating Occupational Exposure
with Passive Dosimetry and Biological Monitoring
Advantages
Disadvantages
Passive Dosimetry
Routes and areas of exposure clearly defined1
Routine experimental design and execution
Participant under supervision of investigator
Generic data bases may be created
Biological Monitoring
Actual dose may be measured1
Unnecessary to adjust for value of garment/protec-
tive clothing
Dermal and respiratory absorption must be esti-
mated1
Extrapolation from patch to body surface area
must be made
Not all exposure scenarios are amenable
Pharmacokinetics must be known1
Routes of exposure cannot be distinguished
Difficult to ensure participant cooperation
Potential problems when using invasive tech-
niques required for specimen collection
1 These factors considered most important.
(3) Problems with the simultaneous use of passive dosimetry and
biological monitoring, (i) The simultaneous application of passive dosim-
etry and biological monitoring has been explored by several groups. At-
tempts have been made to establish a correlation of exposure measure-
ments by both methods. Passive dosimetry has been combined with urinary
metabolite determinations to compare worker exposure as a function of
application method under paragraph (h)(93) and (h)(7) of this guideline;
formulating plant worker exposure under paragraph (h)(8) of this guide-
line; and homeowner exposure under paragraph (h)(85) of this guideline.
Numerous other studies have similarly attempted to correlate exposure esti-
mates obtained by the use of patches with urine levels of pesticide and/
or its metabolites under paragraphs (h)(52), (h)(53), (h)(35), (h)(37),
(h)(91), (h)(92), and (h)(93) of this guideline. In most of these studies,
no clear cut correlation was found between exposure estimated by both
methods.
(ii) A publication under paragraph (h)(37) of this guideline reported
a good correlation between urinary metabolites and amount of active ingre-
dient (azinphosmethyl) sprayed. More relevant to the subject, a comparison
was also made between dermal exposure estimates derived from urinary
metabolites and patches for the same studies. Both methods gave com-
parable estimates at one application rate, but biological monitoring proved
more responsive to variations in the application rate. For two application
rates differing by a factor of 2.5, passive dosimetry estimated essentially
identical dermal exposure while biological monitoring estimates reflected
the difference in application rates. It should be noted, however, that the
results reported in the Franklin study were obtained by the concurrent ap-
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plication of passive dosimetry and biological monitoring methods on the
same individuals. Unfortunately, the results as obtained did not allow a
conclusive assessment of potential interferences arising from the simulta-
neous use of both monitoring approaches. This concern is discussed in
more detail in paragraph (c)(3)(iii) of this guideline.
(iii) A careful analysis of the information available on the simulta-
neous use of passive dosimetry and biological monitoring suggests that
if a registrant chooses the latter for exposure measurements, no direct der-
mal exposure methods should be used concurrently on the same individ-
uals. This becomes necessary because the trapping devices used in passive
dosimetry for estimating dermal exposure, by definition, intercept chemical
residues. This prevents potential absorption, introducing an unnecessary
and potentially confounding variable into the study. Until proper experi-
mentation clarifies this situation, the Agency discourages the concurrent
use of passive dosimetry and biological monitoring on the same individual
in exposure studies.
(iv) It may be possible to design a study that would allow correlation
between passive dosimetry and biological monitoring methods. An exam-
ple might be to alternate the two monitoring methods, using the same
group of individuals and allowing enough time in between so as to mini-
mize possible interference. The Agency strongly encourages research in
the area of comparing exposure estimated by passive dosimetry and bio-
logical monitoring.
(v) Specific criteria which must be met before proceeding with an
exposure study are described in OPPTS 875.1100 through 875.1400 for
passive dosimetry and in OPPTS 875.1500 for biological monitoring.
(d) New approaches to field studies using passive dosimetry—(1)
Method development. Improving test methodology for measuring expo-
sure, as in all areas of scientific research, is an ongoing process. However,
little progress has been made in developing new methodology post Durham
and Wolfe. The Agency strongly encourages new method development and
stresses that the methodologies detailed herein are subject to change. Re-
search in developing innovative and more efficient ways of measuring der-
mal and inhalation exposure would be of obvious benefit to those estimat-
ing the level of risk to persons handling pesticides.
(2) Examples of recent developments, (i) Several alternative meth-
ods have recently been developed and used in the field. The World Health
Organization, under paragraph (h)(94) of this guideline, proposed the use
of entire portions of garments, rather than patches, to test dermal exposure.
This approach has distinct advantages and disadvantages.
(A) One advantage of collecting residues using clothing that covers
an entire part of the body is that it provides a more thorough representation
of the areas being measured, thus eliminating the uncertainty associated
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with extrapolation from pads. Unfortunately, it is very difficult to change
clothing or underclothing after each exposure period under conditions usu-
ally encountered in the field. Also, it is nearly impossible to remove these
garments without contaminating them with residues from other areas of
the body, especially those on the workers' hands and hair. When using
entire items of clothing, adequate preextraction of interfering additives re-
quires large volumes of solvent, extensive extraction equipment, and
lengthy extraction periods. These problems also arise when extracting the
items of clothing from the field in the laboratory. Experimentation may
lead to the discovery of methods that could make exposure monitoring
less troublesome and more accurate. An example is the measurement of
exposure to fumigants. Popendorf et al., under paragraph (h)(73) of this
guideline, used charcoal impregnated cloth (hand dosimeters) to measure
hand exposure to 1,3-dichloropropene. The treated cloth measures dermal
exposure to ambient air levels as well as direct contact. The hand dosim-
eter introduces an alternative method of measuring hand exposure that may
lessen the burden of a troublesome task.
(B) Fluorescent tracers may be useful in quantifying exposure beneath
clothed areas. Franklin et al., under paragraph (h)(35) of this guideline,
added a fluorescent whitening agent (FWA) to azinphosmethyl in the spray
mixture. After removing the exposed pads and clothing, each applicator
was examined with ultraviolet light. Unclothed areas such as the face and
neck were not monitored with pads, but the tracer revealed that these were
significant areas of exposure. The tracer was also found beneath the pro-
tective and ordinary clothing, confirming the qualitative penetration of dye,
and supporting the concept that there may have been penetration of
azinphosmethyl as well.
(C) A similar experiment was conducted by Fenske et al., under para-
graphs (h)(32) and (h)(33) of this guideline. The tracer, 4-methyl-7-
diethylaminocoumarin, was added at the rate of 300 g to each 5 Ib bag
of diazinon 50 percent wettable powder. The tracer concentration on the
exposure pads and on the subjects was evaluated through a scanning tele-
vision apparatus. There was a discrepancy in the amount of tracer actually
found on the face and the amount that had been estimated. The pad tech-
nique estimated much more exposure to the head than the tracer indicated.
(ii) New approaches for measuring applicator exposure will be accept-
ed if they can be shown to be comparable or superior to the methods
described in these guidelines. Registrants are encouraged to explore and
discuss new approaches and techniques with the Agency before submitting
protocols for approval.
(e) Measuring applicator exposure—(1) A historical perspec-
tive.Shortly after the first acutely toxic synthetic insecticide, parathion, be-
came widely used in agriculture, a number of worker poisonings resulted.
It became evident that quantification of occupational exposure to pesticides
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would be a vital link to evaluating worker safety. In order to minimize
occupational exposure to pesticides, it was necessary to determine the
routes and amounts of exposure that workers received while engaged in
various activities.
(i) The first pesticide exposure study was reported by Griffiths et al.
under paragraph (h)(42) of this guideline. They determined the amounts
of parathion trapped on respirator filter discs to compare the exposure re-
ceived during applications to citrus, by either hand spray guns or airblast
sprayers. Batchelor and Walker, under paragraph (h)(3) of this guideline,
expanded exposure monitoring by including pads attached to workers'
clothing to estimate potential dermal exposure. This allowed the deter-
mination of both the total potential for exposure associated with various
tasks and the relative contribution by the dermal and respiratory routes.
Durham and Wolfe, under paragraph (h)(20) of this guideline, reviewed
all methodology that had been used to monitor pesticide exposure and pro-
vided some experimental validation for the best of that methodology. Sub-
sequent to these pioneering studies, a number of investigators have utilized
minor modifications of the original monitoring technique. However, little
significant improvement in the accuracy of exposure assessment has been
provided by these modifications.
(ii) With the advent of the rebuttable presumption against registration
(RPAR) process by the EPA, the ultimate use of exposure monitoring data
was drastically changed. It could no longer be used simply as a basis for
the recommendation of the safest application procedures or as a guide for
dealing with acutely toxic hazards. Now, quantitative assessments of risk
for specific deleterious effects are required. These effects may be the result
of a subtle physiological event resulting from chronic exposure. Therefore,
the exposure workers will receive during use of pesticides must be esti-
mated as reliably as possible. The purpose of these guidelines is to suggest
the best methods currently available for this estimation.
(iii) Most of the methods recommended in these guidelines have been
extensively reviewed under paragraphs (h)(14), (h)(20), and (h)(96) of this
guideline. This guideline borrows heavily from those reviews, with the
intent of providing the users of these guidelines with a single source of
historical information and justification for the selected methods. Some of
the more recently developed methods currently in use may prove superior
to those detailed in these guidelines. The methods discussed here have
been shown to be satisfactory in field use and were used to collect the
majority of exposure data available at this time. Other methodologies dem-
onstrated to be effective will of course be accepted by the Agency.
(iv) The following abbreviated review of exposure monitoring by pas-
sive dosimetry is divided into dermal and respiratory exposure, with major
emphasis on the former. Dermal monitoring is subdivided into exposure
for all areas of the body with a separate section for hand exposure. Also
12
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included under dermal monitoring are the body surface area values and
a discussion of exposure due to the penetration of clothing by pesticides.
(v) A very important consideration that must be kept in mind when
selecting methods for exposure monitoring is that the monitoring method
should not subject the participants to any more exposure than is absolutely
necessary. For instance, if the pesticide label specifies that respirators that
have been approved by the National Institute for Occupational Safety and
Health (NIOSH) must be worn during application, no method may require
a participant to wear a respirator that would provide less protection. Every
monitoring method must be chosen to ensure that human safety will not
be compromised.
(2) Dermal exposure monitoring—(i) Monitoring of exposure to
all areas of the body except the hands. (A) The amount of pesticide
potentially available for absorption through the skin of a worker can be
estimated by trapping the material before it contacts the skin, or by remov-
ing material that has contacted the skin before it has been absorbed. This
is done using various types of pads or articles of clothing to trap impinging
residues, or by removing residues from the skin by swabbing or rinsing
with an appropriate solvent.
(B) A major portion of currently available data concerning dermal
exposure to pesticides was collected using a-cellulose and multilayered
gauze pads described by Durham and Wolfe under paragraph (h)(20) of
this guideline. However, other investigators have employed cellulose filter
paper discs (Batchelor and Walker, under paragraph (h)(3) of this guide-
line); combined filter paper and surgical gauze pads (Lavy et al., under
paragraph (h)(51) of this guideline); entire items of clothing (Miller et
al., under paragraph (h)(65) of this guideline); patches cut from various
types of fabric and backed with surgical gauze to collect residues that
penetrate the fabric (Knaak et al., under paragraph (h)(47) of this guide-
line); skin swabbing (Durham and Wolfe, under paragraph (h)(20) of this
guideline); and pads impregnated with lanolin to simulate the slightly
greasy surface of the skin (Fletcher et al., under paragraph (h)(34) of this
guideline).
(C) If pads are used to entrap residues that would have impinged
on the skin, the material used for construction of the pads must be absorb-
ent enough to retain all the liquid that contacts them, or if used for collect-
ing dusts or dried residues, must be porous enough to collect these mate-
rials. The pads must be strong enough to hold up under the abuse they
will receive in the field. They must not contain additives such as sizing
that will interfere with the chemical analysis of extracted residues. Addi-
tives can usually be removed by preextraction of the pads. However, some
interfering compounds cannot be adequately removed to allow analysis of
low levels of residue. Cellulose filter paper pads are usually unsatisfactory
13
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because they are quickly saturated with spray and do not have the nec-
essary mechanical strength.
(D) Pads constructed from several layers of filter paper covered with
multiple layers of surgical gauze may eventually prove to be a superior
monitoring device. The filter paper readily absorbs liquids while the gauze
collects impinging dry residues and provides extra mechanical strength.
Unfortunately, use of this type of pad under actual field conditions has
been rather limited. Therefore, data regarding the trapping efficiency of
these pads is also limited.
(E) Another problem encountered when using external pads to mon-
itor dermal exposure is the need to estimate how much of the material
collected on the pads would have eventually penetrated clothing. Monitor-
ing dermal exposure with pads constructed from squares of fabric backed
by an absorbent pad can provide the investigator with a rough estimate
of how much residue would have penetrated through the clothing to the
skin of the worker. However, there are also problems associated with this
type of pad. Pretreatment of the fabric, special finishes, and the type of
fabric used can influence the collection, retention and penetration of resi-
dues. Also, use of this type of pad only provides simulation of the penetra-
tion of residues through freshly laundered clothing during the first expo-
sure period of the day. These problems will be discussed in greater detail
in paragraph (2)(iv)(C), concerning exposure due to residues that penetrate
clothing.
(F) Some dermal exposure monitoring techniques have proved to be
less than advantageous. Fletcher et al., under paragraph (h)(34) of this
guideline, found that analytical difficulties encountered when using their
lanolin impregnated pads made the use of this type of monitoring device
impracticable. Skin swabbing is a laborious way to monitor dermal expo-
sure. Durham and Wolfe, under paragraph (h)(20) of this guideline, found
that it took 25 strokes with each of four ethanol soaked swabs to remove
an average of 91 percent of the total amount of parathion that was depos-
ited on the hands.
(G) Taking into account the advantages and disadvantages of the var-
ious monitoring devices listed above, the simple o-cellulose and multi-
layered gauze pad methods are recommended for monitoring dermal expo-
sure to pesticides. Durham and Wolfe, under paragraph (h)(20) of this
guideline, first described the construction and use of these monitoring de-
vices. Davis, under paragraph (h)(14) of this guideline, repeated much of
this work and included information on validation of methodology and
problems encountered during field monitoring. Durham and Wolfe, under
paragraph (h)(20) of this guideline, also reported on the testing of these
monitoring devices. They demonstrated the effectiveness of a-cellulose
pads in reflecting the amount of pesticide deposited on spraymens' fore-
arms. This was accomplished by comparing the residues found on pads
14
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to those found on adjacent areas of skin swabbed with ethanol. Unfortu-
nately, they did not carry out a similar study to determine how well multi-
layered gauze pads reflect the ability of skin to entrap dry residues. How-
ever, they did test the ability of these pads to retain dusty residues. When
dust was applied to the surface of these pads, and the pads were inverted
and shaken mechanically, approximately 90 percent of the applied dust
was retained. Both of these types of pads are easy to construct and use.
High quality materials are available for their construction, and if such ma-
terials are used, preextraction is usually not necessary. Extraction of resi-
dues from both these types of pads is relatively easy to perform and extrac-
tion efficiencies are usually very high.
(H) The practicality of a-cellulose and multilayered gauze pads has
been demonstrated by their usefulness in collecting field data for over 25
years. Most applicator dermal exposure data were collected using these
dosimeters. It is imperative that applicator exposure data collected in the
future be at least comparable to the existing data base. If dermal exposure
data are to be collected using any other methodology, an appropriate dem-
onstration of the comparability or superiority of that method should be
included in the study protocol when it is submitted for review.
(ii) Monitoring hand exposure. Any brief review of the literature
concerning dermal exposure of pesticide applicators will demonstrate the
important contribution of hand exposure. To illustrate this, references on
hand exposure to workers during various spray operations are shown in
the following Table 2.
Table 2.—Contribution of Hand Exposure to Total Potential Dermal Exposure for Pesticide
Applicators
Activity
Hand exposure as
percent of total dermal
exposure
Reference (under para-
graph (h) of this guideline)
Drivers of tractors equipped with canopies
during air-blast spraying of citrus
Bulk spray suppliers for above application
Drivers of ordinary tractors during boom
spraying of tomatoes
Applicators using hand guns to spray aquatic
weeds from airboats
Drivers for airboats for above application
Aerial applicators
Flaggers for above application
Applicators spraying lawns, trees, and gar-
dens with power sprayers
Applicators spraying lawns with hose-end
sprayers
41
52
25
47
89
55
39
37
98
(93)
(93)
(94)
(94)
(94)
(63)
(63)
(55)
(17)
(A) The exposure of workers' hands to pesticides has been monitored
with lightweight absorbent gloves or sections cut from the back and palm
of such gloves (under paragraphs (h)(16) and (h)(91) of this guideline)
15
-------
or by swabbing or rinsing the hands with various solvents in several dif-
ferent ways (under paragraphs (h)(20), (h)(90), and (h)(61) of this guide-
line). All of these methods except those that employ absorbent gloves will
not remove residues that are absorbed into the skin during the exposure
period. However, the use of absorbent gloves may overestimate hand expo-
sure. Even smooth surfaced nylon gloves may retain several times more
residue than would have adhered to flesh (under paragraph (h)(16) of this
guideline). Since hand exposure is often such a large component of total
exposure, the use of gloves may result in a significant overestimation of
total dermal exposure.
(B) Gloves also contain foreign materials such as sizing which may
be difficult to remove by preextraction and which may interfere with
chemical analysis of low levels of residue. Swabbing the hands with sol-
vent is not satisfactory because of difficulties in adequately removing resi-
dues from between the fingers and around the fingernails. Durham and
Wolfe, under paragraph (h)(20) of this guideline, found that they could
recover approximately twice as much residue from workers' hands by
using a bag rinse method rather than swabbing. Washing the hands in a
stream of solvent or in a basin containing solvent is probably as effective
and faster than shaking the hands in plastic bags containing solvent, but
is not as standardized or as convenient as the bag rinse.
(C) A problem with any washing procedure is finding a solvent that
will provide adequate removal of residues without causing injury to the
skin or increased absorption of a pesticide. For many years, hundreds of
contaminated workers' hands have been rinsed with 95 percent ethanol,
water, or water containing detergent, without evidence of skin injury or
increased absorption of pesticides. However, there have been several in-
stances of problems with degradation of residues or interference with anal-
yses due to the solvent used.
(D) Most existing hand exposure data were collected using some type
of rinsing procedure and it is imperative that any such data collected in
the future be comparable to the existing data base. Therefore, it is rec-
ommended that exposure of the hands be assessed by washing and the
most convenient washing procedure for use in the field is the bag rinse
method developed by Durham and Wolfe under paragraph (h)(20) of this
guideline. Lightweight monitoring gloves have also been routinely used
and this technique is also acceptable to the Agency. If a registrant elects
to employ some other procedure, it will be necessary to obtain prior Agen-
cy approval for the data to be acceptable.
(iii) Additional considerations—(A) Use of dermal pads. After an
investigator has determined which monitoring devices and processes are
suitable for the exposure situation being studied, there are still several
questions that must be answered before monitoring can begin. These are:
how many dermal pads are required to assess each exposure and where
16
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should these pads be located on the workers; how many replicate expo-
sures are necessary and what constitutes a replicate; what monitoring is
necessary when the workers are required to wear protective garments; and
how long is an acceptable exposure period? Enough data must be gathered
so that the exposure estimates resulting from the study will reflect the
range and magnitude of exposure that a typical user of the pesticide will
receive. When all the resources necessary for planning, implementing, and
completing an exposure study are addressed, extra replicates or extra pad
locations should be considered to ensure valid conclusions.
(B) Number and location of dermal pads. (1) Most investigators
have essentially adopted the number and location of dermal pads used by
Durham and Wolfe (see paragraph (h)(20) of this guideline). They rec-
ommended that each worker be monitored with a set of 10 pads. The
Agency requires the use of at least 10 pads attached at the following loca-
tions:
(/) In front of the legs just below the knees.
(if) In front of the thighs.
(Hi) In back of the forearms.
(iv) On top of the shoulders.
(v) In back of the neck at the edge of the collar.
(vi) On the upper chest near the jugular notch.
Moving these pads to locations other than those specified must be ap-
proved by the Agency. However, the investigator is free to include any
additional pads he feels necessary for a better estimation of exposure, e.g.
head patches. The relationship of these pads to various areas of the body
will be discussed in a following section.
(2) Assuming that the workers' shirts and trousers will be constructed
of different materials and that one will want to estimate how much residue
will penetrate the clothing, extra pads could be attached under the appro-
priate clothing. These pads should be placed adjacent to but not covered
by one of the outer pads. The locations chosen for these extra pads should
be in areas of the body that are expected to receive the highest exposure.
Pesticide penetration of clothing will also be discussed in a later section.
(3) If it is suspected that an exposure situation will result in extraor-
dinary exposure to an area of the body that is not well represented by
the normal pad locations, pads should be moved or extra pads added to
assess such exposure. For example, if a mixer often carries large bags
of a dry formulation, the investigator would need to move the forearm
pads to the inside of the arms and add an extra pad on the stomach to
17
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determine exposure that occurred in these areas due to contact with the
outside of bags.
(4) To reduce laboratory work, pads from opposite sides of the body
can be combined prior to extraction. However, the back and chest pads
cannot be combined, as separate residue values are needed from these pads
for calculations. Also, pads from opposite sides of the body should not
be combined if one of these pads is to be used in conjunction with an
adjacent pad under the clothing to assess penetration.
(5) It is advised that supervisors instruct workers participating in the
study to avoid touching the exposure pads. Some investigators have found
it useful to employ photographic records to assist in the documentation
of pad placement.
(C) Monitoring when workers are required to wear protective
garments. If the pesticide being studied is, or will be, registered for use
only when wearing protective garments, dermal monitoring is slightly dif-
ferent. In addition to the standard external patches, the Agency may require
that investigators monitor workers with extra pads under the protective
garments to assess penetration. These pads should be located in regions
that are expected to receive maximum exposure such as beneath garment
seams. Since the maximum exposure or area of penetration cannot always
be accurately anticipated, additional pads should be placed under un-
seamed areas of protective garments in all the same locations as specified
for dermal exposure monitoring of workers not wearing protective cloth-
ing. Pads under protective garments should be near, but not covered by
any pads on the outside of the clothing. Even if the label specifies that
protective gloves must be worn, hand exposure under the gloves must be
assessed. Maddy et al., under paragraph (h)(62) of this guideline, as well
as other investigators, have clearly demonstrated that workers, even when
wearing rubber gloves, can receive significant hand exposure.
(D) Acceptable exposure periods. (7) It is difficult to specify in ad-
vance the optimal exposure period to monitor. This will depend on the
nature of the material being applied and the activity being studied. The
ideal period is long enough to collect sufficient residue for analysis but
not so long that there is significant loss of residue through evaporation,
absorption, or chemical conversion.
(2) Serat et al., under paragraph (h)(78) of this guideline, found sig-
nificant losses of both parathion and dicofol after fortified fabric patches
were exposed to ambient conditions for 4 to 6 h. Their tests included cot-
ton gauze but not a-cellulose pads. However, Durham and Wolfe, under
paragraph (h)(20) of this guideline, detected no loss of either parathion
or DDT from a-cellulose pads compared to worker's fore-arms, unless
the loss occurred at the same rate from both surfaces. They did not specify
the exposure period, but usually monitored workers for 30 min to 2 h.
18
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(3) It is also convenient to change monitoring media and perform
hand rinses at some natural break in the workers' schedule. The items
shown in the following Table 3. will provide some idea of exposure peri-
ods that have proven useful for monitoring various activities.
Table 3.—Exposure Periods from Selected Pesticide Exposure Monitoring Studies
Activity
Ground-sprayer application
Mixing/loading for above application
Pilots for aerial application
Mixing/loading for above application
Flagging for above application
Application to crawl spaces or around slab foun-
dations for termite control.
Tractor drawn low-pressure boom sprayers
Backpack type hand sprayers
Application to lawns and shrubs with compressed
air or hose-end sprayers.
Air blast aoDlication to orchards
Exposure Period
30 to 120 min
10 to 30 min
1 to 1 0 h
1 to 1 0 h
1 to 7 hrs.
1.5 to 2 h
2 h
3 to 4 h
15 to 30 min
20 min to 2 h
Reference (under paragraph
(h) of this guideline)
(62)
(69)
(61)
(14)
(14)
(17)
(961
(iv) Dermal exposure calculations. After the amount of residue on
a unit area of exposure pad during a unit time of exposure has been deter-
mined, several assumptions are used to estimate the worker's potential der-
mal exposure. It is necessary to extrapolate the amount of pesticide found
on each unit area of pad to the amount that would have impinged on the
total body region represented by the pad. This assumes that certain pads
represent certain regions of the body and that the surface areas of these
regions are known. An assumption would also be made as to how much
of the residue found on a pad would have penetrated the worker's clothing.
(A) Assumptions concerning the surface area of regions of the
body and pad locations that represent these regions. (7) Most of the
literature describing pesticide exposure monitoring (refer to paragraphs
(h)(14), (h)(20), and (h)(96) of this guideline) has recommended the use
of surface areas based on the method of Berkow (under paragraph (h)(4)
of this guideline). Popendorf and Leffingwell (under paragraph (h)(72) of
this guideline) examined the surface area values that several investigators
proposed for various regions of the human body. They concluded that ex-
trapolating exposure from the pad to the body region using Berkow's
method is inappropriate because Berkow specifically adjusted body region
surface areas for their relative importance to burn victims. Popendorf and
Leffingwell (under paragraph (h)(72) of this guideline) developed regional
surface areas based on anatomic modeling of the 50th percentile man.
(2) The Exposure Assessment Group/Office of Health and Environ-
mental Assessment (OHEA) (under paragraph (h)(31) of this guideline)
investigated previous research on the surface area of body regions. Based
on this review, the model
19
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SAP = a0WalHa2
where
SAP is body part surface area in meters squared,
W is body weight in kilograms,
H is height in centimeters,
ao, ai, and a2 are constants for each body region.
was developed and compared to data collected from the Second Na-
tional Health and Nutrition Examination Study (NHANES II). The coeffi-
cient of determination for adult males was greater than 0.7 for all body
regions with the exception of the head, upper arms, hands and feet. Foot
exposure is rarely measured, and hand exposure is measured directly using
hand rinses or cotton gloves.
The following Table 4. shows the surface area estimates presented
by Berkow and those derived from the OHEA report. A comparison of
the two sets of estimates shows close agreement for the trunk area, fore-
arms, and lower legs. The OHEA estimates for upper arm and thigh sur-
face areas are substantially greater than the Berkow estimates.
Table 4. — Surface Areas for Regions of the Adult Male Body
Region of the Body
Head
Face
Trunk2
Back of Neck
Front of Neck
Chest/Stomach
Back
Upper Arms
Forearms
Hands
Thighs
Lower Legs
Feet
Surface Area of Region
(Berkow)
(cm2)
650
110
150
3550
3550
1 320
1,210
820
2,250
2380
Surface Area of Region
(OHEA)1
(cm2)
1 300
7,390
_
_
2910
1,310
990
3,820
2560
1.310
1 for 50th percentile man (NHANES II, under paragraph (h)(31) of this guideline).
2 Includes the neck.
(4) The Agency recommends that the surface areas presented in the
following Table 5. be used in calculating exposure to body regions. For
consistency with past practices and in recognition that the Berkow and
OHEA estimates closely agree, the Berkow estimates have been retained
with the exception of the upper arms and thighs. The OHEA estimates
for the thighs and upper arms have replaced the Berkow estimates.
20
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Table 5.—Surface Areas for Regions of the Adult Body and Locations of Dermal Exposure Pads
that Represent These Regions
Region of the Body
Head
Face
Back of Neck
Front of Neck3
Chest/Stomach
Back
Upper Arm
Forearm
Hand
Thigh
Lower Leg
Feet
Surface Area of Region
(cm2)
1,3001
650
110
150
3,550
3,550
2,910
1,210
820
3,820
2,380
1.310
Location of Pads
Representing Region
Shoulder, Back, Chest2
Chest
Back
Chest
Chest
Back
Shoulder and Forearm/
Upper Arm
Forearm
Thigh
Shin
1 Surface area for the head includes the 650 cm2 face surface area.
2 Exposure to the head may be estimated by using the mean of the shoulder, back and chest patch-
es, or by using a head patch.
3 Includes "V" of the chest.
(5) Davis, under paragraph (h)(14) of this guideline, suggested that
certain exposure pads be used to represent various regions of the body.
However, his representation of vertical facial areas by horizontal shoulder
pads may well lead to the overestimation of facial exposure. Therefore,
it is recommended that future exposure studies employ the pad locations
shown in Table 5. for extrapolation from residues found on dermal pads
to exposure estimates for adjacent regions of the body.
(B) Penetration of residues through clothing. (7)The problem of
accounting for protection from exposure by a worker's clothing is not eas-
ily dealt with because of the scarcity of appropriate data. Assumptions
ranging from complete protection of covered areas (under paragraph
(h)(20) of this guideline) to complete lack of protection (under paragraph
(h)(93) of this guideline) have been used to circumvent this problem.
Maddy et al., under paragraph (h)(62) of this guideline, monitored a total
of 102 individual exposure situations of mixers, loaders, flaggers, and ap-
plicators. They found that an average of approximately 23 percent of total
dermal exposure was due to residue that penetrated 7-oz, 65 percent Da-
cron polyester, 35 percent cotton twill coveralls. Gold et al., under para-
graph (h)(40) of this guideline studied the exposure of 38 urban applicators
and found that the mean penetration of carbaryl through clothing was only
6.1 percent. Their data appeared to indicate that penetration was not greatly
affected by formulation (2.4 percent to 11 percent penetrated), crop (2.3
percent to 11 percent penetrated), or type of application equipment used
(4.7 percent to 16 percent penetrated). The same group of investigators
(Leavitt et al., under paragraph (h)(54) of this guideline) also studied the
penetration of carbaryl to the skin of five professional applicators wearing
jumpsuits of unspecified material with open collars and short sleeves. The
workers used power sprayers to treat trees and their exposure resulted from
21
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mixing, applying and equipment cleaning. An average of 5 percent of the
material that contacted their clothing penetrated to the skin. Although the
mean values of total pesticide contacting the different regions being mon-
itored ranged from 0.84 to 13 (ig/cm2/h, the average amounts that pene-
trated ranged from 3.4 to 6.9 percent. Spear et al., under paragraph (h)(82)
of this guideline, and Popendorf et al., under paragraph (h)(71) of this
guideline, reported that up to approximately 50 percent of pesticide resi-
dues impinging on the clothing of fruit harvesters would have penetrated
to the skin. Freed et al., under paragraph (h)(38) of this guideline found
that up to approximately 50 percent of the active ingredient from simulated
sprays penetrated a 65 percent polyester, 35 percent cotton fabric, but that
100 percent cotton fabric was much more resistant to penetration.
(2) Because existing data indicate such extreme variability in perme-
ation and/or penetration of clothing (including protective) by pesticides,
study investigators should consider laboratory testing procedures to supple-
ment field studies in some cases. The Agency believes that laboratory test-
ing of a variety of protective clothing materials would provide additional
valuable data, since it is unrealistic to assume that all users of a particular
pesticide product would wear exactly the same type of protective clothing.
Registrants are encouraged to discuss study design involving protective
clothing or equipment performance with Agency personnel before submit-
ting protocols for approval.
(3) Respiratory exposure monitoring—(i) Exposure to applicators.
(A) When equipment used for monitoring respiratory exposure during the
application of pesticide sprays has been properly designed, it is found that
respiratory exposure is usually a very small component of total exposure.
This is demonstrated by the first five exposures shown in the following
Table 6. Assuming that 100 percent of the material that is potentially avail-
able for respiratory exposure is absorbed, a situation is rarely found where
the respired dose would be a significant portion of the total dose received
during normal spray operations. However, as illustrated by the last two
lines of the following Table 6., there are situations when respiratory expo-
sure can be significant. These situations usually involve the application
of dusts, aerosols, and fumigants or the application of sprays in enclosed
spaces. Also, as the dermal penetration of the pesticide decreases, the rel-
ative importance of the inhalation route becomes greater.
22
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Table 6.—Contribution of Respiratory Exposure to Total Potential Exposure for Pesticide
Applicators
Activity
Drivers of tractors equipped with canopies during
air-blast spraying of citrus.
Bulk spray suppliers for above application
Drivers of ordinary tractors during boom spraying
of tomatoes.
Applicators using hand guns to spray aquatic
weeds from airboat.
Drivers of airboats for above application
Applicators using aerosol generator for mosquito
control.
Applicators using hand knapsack mister for
spraying tomatoes.
Physical
Form of
Pesticide
Used
Spray
Unspecified
Spray
Spray
Spray
Aerosol
Mist
Respiratory
Exposure as
percent of
Total
Exposure
0.029
0.004
0.04
none detect-
able
none detect-
able
9.1
3.1
Reference (under
paragraph (h) of this
guideline)
(93)
(93)
(94)
(94)
(94)
(11)
(81)
(B) In view of the preceding, registrants may not be required to mon-
itor for respiratory exposure unless the Agency has reason to believe that
such exposure would be significant. However, respiratory exposure mon-
itoring will be required if the material in question has been demonstrated
to cause an adverse biological effect that is associated with or accentuated
by respiratory exposure; if the formulation or application method is ex-
pected to result in significant respiratory exposure; or if the formulation
or application method has an unknown potential for respiratory exposure.
(iii) Choice of method. No single methodology can be specified as
best for respiratory exposure monitoring in all cases. The method of choice
will depend on the chemical and physical nature of the material being
studied and may also depend on the activity being monitored. An ex-
tremely wide variety of methods are available. Investigators concerned
with such monitoring are referred to the following extensive reviews. The
methodology used for personal air monitoring was reviewed by Linch,
under paragraph (h)(59) of this guideline. However, he did not emphasize
sampling media that are most useful for the collection of pesticides. On
the other hand, Van Dyk and Visweswariah, under paragraph (h)(88) of
this guideline, reviewed the various media available for collection of pes-
ticides but with major emphasis on high volume sampling. One of the
latest and most complete reviews of all methodology used for field mon-
itoring of airborne pesticides was by Lewis, under paragraph (h)(56) of
this guideline. Other sources of information that will be of help in planning
and implementing studies of respiratory exposure to pesticides are the pro-
tocol under paragraph (h)(57) of this guideline and articles under paragraph
(h)(14) and (20) of this guideline.
(iv) Personal monitoring of respiratory exposure. (A) These guide-
lines require that potential exposure by the inhalation route be estimated
23
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using personal monitors. Several techniques are available to the investiga-
tor. These range from simple gauze pads used in place of dust filters in
modified respirators to rather exotic solid sorbents used with battery-pow-
ered personal air samplers. The various media and pumping systems that
may be applicable have been reviewed under paragraphs (h)(56) and
(h)(59) of this guideline.
(B) The gauze pad procedure (under paragraph (h)(20) of this guide-
line) is convenient because it is simple to construct the necessary pads
and to modify the respirators, and exposed pads can usually be extracted
in the same manner as exposed dermal pads. Also, the test subject pro-
duces the air flow for trapping so that breathing rate and total volume
inhaled do not have to be estimated separately. However, the investigator
must ensure that the respirator pads are an efficient trap for the material
under study, that the respirator is well fitted to the test subject's face,
and that the subject does not remove the mask during the exposure period.
Construction of respirator pads, details of respirator modification, and a
description of field operations used with this procedure appear in para-
graph (i)(3) and (4) of this guideline.
(C) In the past, the second most commonly employed procedure for
assessing respiratory exposure to pesticides under field conditions utilized
ethylene glycol as a sampling medium. The use of this material in midget
impingers presents some problems for personal monitoring since the liquid
is easily spilled as a worker goes about his duties and the liquid may
also be drawn into the pump mechanism. These problems may be allevi-
ated by using the "spill-proof microimpingers described by Linch, under
paragraph (h)(59) of this guideline. Even with spills eliminated, this proce-
dure, as with all procedures employing a mechanical pump, requires an
estimation of a worker's ventilation rate. This varies with the amount of
exertion employed. Another problem that may be encountered with this
system is loss of residue. Some materials are not trapped by ethylene gly-
col or are rapidly lost from solution during prolonged sampling. Other
materials are degraded in ethylene glycol, probably by hydrolysis since
the ethylene glycol also traps considerable moisture from the air.
(D) The use of solid sorbents for personal monitoring of pesticide
exposure is gaining in popularity and this technology is developing rapidly.
The major disadvantage of using sorbents, in addition to the need to esti-
mate the worker's ventilation rates, is the restriction of airflow by finely
divided particles. Another drawback is degradation or chemical conversion
of some pesticides bound to active sorbents. A description of the use of
personal monitoring pumps and samplers appears under paragraph (i)(2)
and (4) of this guideline.
(v) High volume air sampling. In atypical cases where levels of toxi-
cants in the air are too low to be sampled by personal monitors or where
suitable monitoring media are not available, investigators may have to re-
24
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sort to the use of high volume samplers. The use of such samplers has
been described in a number of publications (under paragraphs (h)(56),
(h)(57), and (h)(88) of this guideline). These are not generally rec-
ommended for monitoring occupational exposure in the field unless abso-
lutely necessary. For this reason they will not be discussed further in these
guidelines.
(4) Dermal and respiratory exposure monitoring at indoor sites.
(i) In general, monitoring of exposure during application of pesticides at
indoor sites involves the same considerations as monitoring during outdoor
applications. Even though some of the types of sprayers used for indoor
applications may produce aerosols with a greater potential for respiratory
exposure than is generally found for outdoor applications, monitoring
methods that are satisfactory for outdoor applications should also be satis-
factory for indoor sites.
(ii) It has been estimated (under paragraph (h)(27) of this guideline)
that pesticides are used in more than 80 percent of U.S. households. This
fact and several others lead to the special concern one must have for the
exposure of individuals occupying dwellings that have been treated with
pesticides. Indoor residues can persist for significantly greater periods of
time compared to similarly applied outdoor residues (see paragraph (h)(13)
of this guideline). This increased indoor persistence may be due to an envi-
ronment that protects residues from sunlight and moisture, provides for
different degradation pathways, and inhibits their dissipation by limiting
ventilation of vapors. Since modern construction methods have produced
dwellings that are energy efficient and greatly restrict air exchange, they
may exacerbate problems with indoor air pollution (see paragraph (h)(84)
of this guideline).
(iii) It is recommended that the dermal and respiratory exposure of
applicators be monitored using the same methodology that is recommended
for outdoor applications. However, since more respiratory exposure to
aerosols and vapors is expected, the investigator should ensure that the
trapping medium used to assess this exposure is particularly efficient in
trapping these forms.
(iv) For postapplication respiratory exposure monitoring, a battery op-
erated pump fitted with a trapping medium that is an efficient trap for
vapors may also be used. However, the sampler need not be worn by a
test subject, but only placed at breathing level in the room. Since con-
centrations of pesticide vapors may be low after application, the investiga-
tor may have to sample for extended periods to collect enough material
for analysis.
(v) Although one can determine the postapplication levels of residues
on surfaces by swabbing or by the analysis of material on collection sur-
faces such as mylar squares that are left in a room for various periods
25
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of time after application, the Agency does not feel that any satisfactory
system has yet been devised and sufficiently tested to ensure that it will
reliably allow one to relate such residues to the potential for dermal expo-
sure. Therefore, surface residue monitoring is not required. Postapplication
monitoring for estimation of potential dermal exposure will be required,
using the same technique as for monitoring dermal exposure to applicators,
only on a case by case basis and will depend on the type of pesticide
product and its use.
(vi) Since the potential for postapplication respiratory exposure will
be dependent on the nature of the pesticide product used, the sampling
schedule for postapplication respiratory exposure monitoring will have to
be determined in consultation with Agency scientists. This sampling sched-
ule will be created such that the pattern of decline of potential respiratory
exposure as a function of time can be defined.
(f) The use of surrogate data and the development of generic pre-
dictive correlations. (1) Many difficulties and variables associated with
carrying out exposure monitoring studies in the field during actual applica-
tion have been discussed previously in this document. Many of the vari-
ables, such as climatic conditions and the degree of care exercised by indi-
viduals, are not under the control of the scientist supervising the study.
These uncontrolled variables usually result in a wide variation in experi-
mental results. The amount of resources required to do field studies for
every controllable variable (such as crop, application method, or pesticide)
would be very high. For these reasons, and for the scientific reasons dis-
cussed below, the Agency policy (under paragraphs (h)(28) and (h)(76)
of this guideline) is to use "surrogate" data to estimate applicator expo-
sure when appropriate.
(2) "Surrogate" or "generic" exposure data are defined herein as
exposure monitoring data collected for other pesticide chemicals applied
using comparable methods and under similar conditions as for the pesticide
under assessment. The mechanics of the use of surrogate data have been
discussed in detail in public forums and in the published scientific lit-
erature in recent years (under paragraphs (h)(43), (h)(45), (h)(76), and
(h)(79) of this guideline. The assumption in the use of surrogate data is
that in many application scenarios, the physical parameters of application,
not the chemical properties of the pesticide, are most important in deter-
mining the level of exposure. Note that when using a passive dosimetry
monitoring method, what is measured is the amount of chemical impinging
on the skin surface, or available for inhalation, not the actual dose re-
ceived. Factors such as dermal penetration are, of course, expected to be
highly chemical-dependent. A review of all available information on pes-
ticide exposure during application activities, as discussed earlier, supports
the use of surrogate data for applicator exposure assessments.
26
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(3) There is general agreement that the principal application parameter
that determines the level of exposure is the method of application. One
application technique for which there is a great deal of exposure monitor-
ing data is ground application to orchards using high pressure or airblast
equipment. The Agency has evaluated these exposure data to attempt to
derive statistically valid and useful predictive correlations. A significant
correlation was found between application rate and dermal exposure. A
Spearman Rank Correlation Analysis (under paragraph (h)(81) of this
guideline), a test to determine if an increase in exposure is associated with
an increase in application rate, indicated a statistically significant correla-
tion. A less significant correlation was found for another application pa-
rameter, tank concentration.
(4) All of the studies included in the airblast data base are from pub-
lished or publicly available sources. The results of studies carried out by
registrants according to these guidelines, like any other data generated in
support of a registration application or continued registration, may be con-
sidered proprietary, or involve data compensation matters. A proposal has
been put forward, however, to accommodate the routine use of registrant-
generated exposure data on a generic basis so that the overall data base
for estimating applicator exposure would be significantly expanded (under
paragraph (h)(43) of this guideline). The National Agricultural Chemicals
Association, Health Canada, and the Agency actively pursued this pro-
posal.
(5) In June 1992, the Office of Pesticide Programs announced the
availability of the Pesticide Handler Exposure Database (PHED) to reg-
istrants and the public. The development of this generic data base is a
procedure which the Agency will continue to pursue. The Agency believes
that it is more reliable to estimate exposure based on an extensive, scientif-
ically sound and appropriate data base rather than from the results of an
individual study with a limited number of replicates, even if that single
study is judged valid by the Agency. As the Agency receives additional
valid exposure data from any source, the data will be added to the existing
data base, thus expanding that data base and improving its reliability for
estimating exposure for other pesticides. For more information on PHED,
contact the Occupational and Residential Exposure Branch at the Environ-
mental Protection Agency, Office of Pestiide Programs, Health Effects Di-
vision (7509C), 401 M St., SW., Washington, DC 20460.
(g) General information and exposure methodology common to
occupational and residential test guidelines; applicator exposure mon-
itoring, OPPTS Series 875, Group A. (1) The studies carried out accord-
ing to these guidelines will be acceptable to the EPA, but investigators
may find additional helpful information under paragraphs (h)(14), (h)(20),
and (h)(96) of this guideline. The article by Davis (paragraph (h)(14) of
this guideline) should be particularly helpful because it was written as a
27
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primer for those who have never conducted an exposure study. It contains
may practical tips about field operations.
(2) It cannot be overemphasized that investigations carried out accord-
ing to these guidelines must be properly designed to provide for maximum
protection of the study subject's health. Studies conducted to obtain human
exposure data must not violate section 12(a)(2)(P) of FIFRA.
Informed consent should be obtained in writing from all subjects who will
be exposed as a result of these studies, and proposed protocols may need
to be approved by the appropriate human studies committee for the State
in which the exposure will occur. Also, guidelines for the Protection of
Human Subjects of the Department of Health and Human Services should
be considered of the design of such studies (HHS 1981).
(3) Proper administration is vital for successful exposure monitoring
studies, as well as to ensure the safety of the workers being studied. It
is most important that field studies have professional supervision by per-
sons who are knowledgeable and experienced in exposure assessment.
Inexperienced investigators are strongly urged to arrange to accompany
an experienced investigator during an entire exposure study before attempt-
ing a study on their own.
(4) All conditions specified on the label for legal application of reg-
istered pesticides must be observed. Existing or proposed labels with inap-
propriate information concerning protective clothing will be addressed on
a case-by-case basis as protocols are submitted. Chemical resistant gloves,
NIOSH-approved respirators, or any other protective gear that is required,
must not be removed during the exposure monitoring period. Any protec-
tive clothing and equipment required for the workers must not be altered
in any manner that would result in decreased protection.
(5) Studies must be designed so that an exposure is measured sepa-
rately for each activity associated with an application even when, in actual
practice, an individual is involved in more than one activity. For example,
separate estimates shall be made for the exposure received during mixing/
loading the pesticide and while driving the tractor that pulls the ground
boom sprayer. Any differences in the magnitude of exposure for these two
activities may be addressed by different regulatory options. The Agency
recognizes, however, that for certain atypical application scenarios, it
would be impractical to measure exposure for each work activity, and
monitoring of combined activities will be allowed on a case-by-case basis.
(6) Tests must be carried out at label application rates using the actual
formulation and packaging that will be commercially available. The EPA
may require the estimation of exposure to active ingredients, inerts or con-
taminants, any other chemicals present in the formulation, any degradation
or transformation products, or any combination thereof. Also, all data must
28
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be collected and documented in accordance with applicable sections of
Good Laboratory Practice Standards at 40 CFR 160.
(7) Investigators must exercise care to ensure that all operations con-
tributing to the exposure under investigation are carried out in a manner
that is consistent with typical use. Outside applications must be performed
under weather condition (e.g. wind speeds) that are consistent with label
restrictions or that are generally recognized as acceptable for spraying.
Registrants must submit proposed exposure study protocols to the EPA
for review and receive Agency approval prior to initiating the study.
(8) The type and completeness of exposure data required by the EPA
will depend on the toxicity of the chemicals involved, the proposed uses
for the formulation, the proposed methods of application, and the availabil-
ity of data from studies using similar formulations and application meth-
ods. Complete studies will not be required for every product being
registered, and the need for new data is expected to decrease as the expo-
sure data base increases. Exposure data may be required for any method
of application proposed by the registrant.
(9) It is impossible to specify a particular duration of exposure that
would give satisfactory results for a given operation. The exposure period
must be long enough to collect measurable residues, if exposure is occur-
ring, but short enough to avoid excessive losses due to volatilization or
decomposition (refer to Table 3. under paragraph of (e)(2)(iii)(D)(3) of
this guideline for examples of exposure periods that have proved useful
for monitoring various activities).
(10) The Agency requires that each exposure situation be evaluated
using at least 15 replicates. Each replicate is a measure of the exposure
to one worker for one exposure period. To obtain a single "typical" expo-
sure for the situation being studied, individual values must be obtained
under as many different conditions that are expected to affect exposure
significantly as is possible. Three variables that are expected to have the
significant effect on exposure are differences in application equipment,
wind conditions during outdoor application, and, most importantly, dif-
ferent work practices and attitudes toward safety of the study subjects.
Therefore, to obtain a reasonable cross-section of the variation of individ-
ual exposure values, the Agency requires that 15 replicates by obtained
from a minimum of 5 replicates from each of a minimum of three applica-
tion sites. It is strongly recommended that the replicates be obtained using
as many different workers as possible. Fewer replicates will be acceptable
under special circumstances. For example, when applying an experimental
pesticide by air where the availability of subjects is limited, a minimum
of nine replicates obtained from three replicates each at a minimum of
three sites will sufficient.
29
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(11) Many of the supplies and equipment described in these guide-
lines will be followed by a trade name and/or suggested source. This is
meant as a guide to assist locating supplies, constructing dosimeters, or
to describe methods that have been effective in the past. Any mention
of trade names or commercial products does not constitute endorsement
by the Agency, and does not imply that only those items or methodologies
are acceptable. Investigators are encouraged to develop new methods for
measuring exposure that may prove more effective than those described.
(h) References. The following references should be consulted for ad-
ditional background material on this test guideline.
(1) Aitio, A. et al., (eds.). Biological monitoring and surveillance of
workers exposed to chemicals. Hemisphere Publishing Corporation, New
York (1984).
(2) Baselt, R.C., Biological monitoring methods for industrial chemi-
cals. Biomedica Publications, Davis, CA (1980).
(3) Batchelor, G.S. and K.C. Walker, Health hazards involved in the
use of parathion in fruit orchards of North central Washington. A.M.A.
Archives of Industrial Hygiene 10:522-529 (1954).
(4) Berkow, S.G., Value of surface area proportions in the prognosis
of cutaneous burns and scalds. American Journal of Surgery 11:315-317
(1931).
(5) Bradway, D.E. et al., Comparison of cholinesterase activity, resi-
due levels, and urinary metabolite excretion of rats exposed to
organophosphorus pesticides. Journal of Agricultural and Food Chemistry
25:1353-1358(1977).
(6) Calleman, C.J. et al., Monitoring and risk assessment by means
of alkyl groups in hemoglobin in persons occupationally exposed to ethyl-
ene oxide. Journal of Environmental Pathology and Toxicology 2:427-
442 (1978).
(7) Carman, G.E. et al., Pesticide applicator exposure to insecticides
during treatment of citrus trees with oscillating boom and airblast units.
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(1982).
(8) Comer, S.W. et al., Exposure of workers to carbaryl. Bulletin of
Environmental Contamination Toxicology 13:385-391 (1975).
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Agriculture, Nutrition, and Forestry. United States Senate. January, 1979.
p. 21.
30
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(10) Congressional Record. Report on S. 1678 Federal Pesticide Act
of September 19, 1978. H10119
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(12) Davies, J.E. et al., Developments in toxicology and environ-
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(13) Davis, J.E. et al., Persistence of methyl and ethyl parathion fol-
lowing spillage on concrete surfaces. Bulletin of Environmental Contami-
nation and Toxicology 18:18-25 (1977).
(14) Davis, J.E., Minimizing occupational exposure to pesticides: per-
sonnel monitoring. Residue Reviews 75:33-50 (1980).
(15) Davis, J.E. et al., Potential exposure of apple thinners to
phosalone. Bulletin of Environmental Contamination Toxicology 29:592-
598 (1982).
(16) Davis, J.E. et al., Potential exposure of apple thinners to
azinphosmethyl and comparison of two methods for assessment of hand
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(18) Drevenkar, V. et al., The rate of urinary excretion of phosalone
residues in occupationally exposed persons. Science of the Total Environ-
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(19) Drevenkar, V. et al., Occupational exposure control by simulta-
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(20) Durham, W.F. and H.R. Wolfe, Measurement of the exposure
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(21) Durham, W.F., Introduction. Pp. xiii-xiv in Dermal Exposure Re-
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31
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(23) EPA. Chlorobenzilate Position Document 2/3. July 11, 1978, pp.
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(28) EPA. Federal Register 45:42858 (1980).
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(1985).
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32
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the seventh Workshop "Biological Monitoring of Workers Manufacturing,
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(38) Freed, V.H. et al., Minimizing occupational exposure to pes-
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33
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(51) Lavy, T.L. et al., Field worker exposure and helicopter spray
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34
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recent advances in the health sciences and technology. Swedish Council
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