Public Information and Record Integrity Branch
Information Resources and Services Division
(7502C)
Office of Pesticide Programs
Environmental Protection Agency
1200 Pennsylvania Ave., NW.
Washington, DC 20460
RE: Lindane; OPP-34239
World Wildlife Fund (WWF) submits the
following comments regarding the Lindane draft risk assessment.
WWF is a non-profit organization with
over 1.2 million members in the U.S.
WWF is dedicated to using the best available scientific
knowledge to preserve the diversity and abundance of life on Earth
by conserving endangered spaces, safeguarding endangered species,
and addressing global threats to the planet’s web of life.
EPA should retain the full 10X Safety Factor BECAUSE
IT IS A KNOWN ENDOCRINE DISRUPTOR
Lindane is a known endocrine disruptor in
animals and is associated with a range of serious effects on
reproduction and development. These
effects include testicular damage, reduced sperm production,
disrupted estrus (menstrual) cycles, delayed puberty in females,
ovarian and uterine atrophy, infertility (Cooper,1989)
and decreased sexual receptivity (Uphouse,1987)
. Adult male rats treated with lindane develop atrophy of
their sex accessory organs, including the epididymis, seminal
vesicles, and vas deferens, consistent with treatment with an
anti-androgen (Chowdhury,1993)
.The same investigators also identified decreases in
testicular weight and degeneration of the Leydig cells, resulting in
diminished testosterone levels in adult male rats dosed with lindane
(Chowdhury,1994)
Lindane is a weak estrogen, a more potent
anti-estrogen and anti-androgen, and may also interfere with
thyroid, pituitary, and adrenal gland function. Registrant-submitted
data indicate that adult rats of both sexes treated with lindane
develop pituitary and thyroid adenomas while male rats develop
pituitary and thyroid carcinomas(California
Department of Pesticide Regulation; http://www.cdpr.ca.gov/docs/toxsums/toxsumlist.htm)
. Ewes fed lindane have significantly decreased thyroid
hormone (thyroxine) and pituitary hormone (LH) concentrations and
significantly increased insulin and estrogen levels (Rawlings,1998)
. In adult female mice, administration of lindane results in
atrophy of the adrenal glands and abnormalities of the gland
structure. The mice also have increased cholesterol levels and
decreases in ascorbic acid (Vitamin C) content of the glands (Lahiri,1991)
.
Low, environmentally relevant, doses of lindane
inhibit the binding and production of androgens in the prostate,
even at the tiniest dose tested. The inhibition does not appear to
occur via direct binding to the androgen receptor. These
investigators reported a synergistic interaction between malathion
and lindane resulting in inhibition of
testosterone metabolism in the rat prostate (Danzo,1997,
Simic,1992)
.
Congressional and FIFRA SAP concern about endocrine disruption
The passage of FQPA amended the Federal Food, Drug
and Cosmetic Act and required EPA to develop screens and assays for
endocrine disruption. Not only did Congess order EPA to develop
screens and assays, but it also indicated that EPA should consider
endocrine disruption when determining pesticide tolerances.
In 1999, the Office of Pesticide Programs (OPP)
released a document titled “The Office of Pesticide Programs’
Policy on Determination of the Appropriate FQPA Safety Factor(s) for
Use in the Tolerance-Setting Process” (10xpoli.pdf).
The FIFRA SAP panel reviewed this document (final.pdf)
and indicated that, if EPA does not have all relevant information
regarding developmental neurotoxicity, immunotoxicity and effects on
the endocrine system, the Agency “faces a special presumption
against relieving the 10X safety factor” (p. 14).
An additional justification for considering
endocrine disruption to be significant can be found in the National
Toxicology Program (NTP) and National Institute of Environmental
Health Sciences (NIEHS)
Endocrine Disruptors Low Dose Peer Review Report issued in August
2001 (http://ntp-server.niehs.nih.gov).
This report concluded that there was credible evidence that
certain hormone-like chemicals have biological effects at very low
doses. More
importantly, most of the credible data came from developmental
studies evaluating doses and responses not typically looked at in
currently required toxicology tests. The NTP Low Dose Review Panel
recommended modifying the multigenerational protocol that will be
used as the definitive Tier 2 assessment of potential endocrine
activity. The test as
it currently stands may not evaluate some of the critical responses
to detect endocrine activity. For example, linuron and di(isononyl)
phthalate (DINP) have both been shown to have endocrine activity
even though credible multigenerational and prenatal studies were
negative using standard design.
The lindane draft
assessment as written ignores the significance of endocrine
disruption due to delays in screening and testing implementation.
However, more importantly, subjecting lindane in the future to
finalized screens and assays is likely to only confirm what EPA
already knows – that lindane is an endocrine disrupting chemical
in mammals, birds and fish. The FQPA Safety Factor represents one
available mechanism to account for endocrine disrupting effects
until appropriate screens and assays can be developed. In addition,
we note that the lindane multigenerational study (the “gold
standard” for evaluating endocrine disrupting effects) described
in the draft assessment was conducted in 1991, before 1996 guideline
changes which added additional endpoints responsive to estrogenic
and/or androgenic endocrine disruption. (Table 1; summarized from
Federal Register: October 31, 1996; Volume 61, Number 212; Page
56273-56322). EPA faces an unenviable struggle with consistent
application of the FQPA safety factor, but it must not discount
endocrine disruption simply for the sake of consistency with prior
tolerance decisions, particularly if doing so ignores areas of
science especially relevant to embryos, fetuses, infants and
children.
We agree with the comments submitted by the
Natural Resources Defense Council (NRDC) that EPA should not treat
exposures to lindane-treated seeds in isolation, but must take into
account additional sources of exposure to lindane.
These include pharmaceutical uses, pet care, breast milk
contamination, bioaccumulation in fish, and residues from past uses.
We also agree that EPA needs to include the b-HCH
isomer in the assessment as lindane is known to be transformed into
this dangerous isomer in the environment and in living organisms.
THE
EFED INTEGRATED ENVIRONMENTAL RISK ASSESSMENT DOES NOT SUPPORT
LINDANE REGISTRATION
Lindane
risks to birds may be overestimated as birds appear to have a
behavorial (taste) aversion to lindane treated seeds. However, as
discussed in the risk assessment, birds of prey may consume mammals,
resulting in lindane exposure. EPA asserts that aquatic risk may
also be overestimated because they are based on the assumption that
100% of lindane will dissociate from the seed. However, it is
equally plausible that EPA’s RQs are underestimates of risk.
First, as was the case with the Health Effects Division (HED)
assessment, the EFED assessment ignores preexisting lindane
concentrations (and a-HCH or b-HCH
isomers) in wildlife. For example, g-HCH levels in fisher (Martes
pennanti)
brains collected in Wisconsin during 1992-1993 vary; while most were
below the limit of quantitation (LOQ), lindane was detected in 2
females (14 fishers were analyzed) at 0.73 and 6.07 ppb (Gerstenberger,1996)
. HCH concentrations (sum a, b,
g,
d) detected in white-sided dolphin blubber (collected during
1994-1996) and in pilot whales (collected between 1990 – 1996) in
the Gulf of Maine averaged 220 ng/g (220 ppb) and 57.5 ng/g (57.5
ppb) respectively (Weisbrod,2001)
. In addition, lindane concentrations (specific isomers not
identified) in Dreissenid mussels collected from the Southern Great
Lakes ranged from below the limit of detection to 1 ng/g or (1 ppb),
mostly detected in samples from Lake Michigan and central and
eastern Lake Erie (Robertson,1998)
.
In
addition, there is little discussion in the EFED draft assessment of
the implications of using crude toxicity measures (mortality) to
determine acute risk to wildlife species. In determining acute risk
for lindane, estimated environmental concentrations were divided by
the LD50 or LC50 to generate a risk quotient (RQ).
Only in evaluating chronic risk was a
NOAEC or NOAEL used. One can imagine the response from public
health organizations and concerned citizens if EPA were to regulate
acute risk to humans based on how much pesticide was required to
kill 50% of test animals. Thus, the acute RQ could easily
underestimate risk of sublethal toxicity such as endocrine
disruption, developmental toxicity, immunotoxicity, altered behavior
and adverse effects on reproduction. If human health assessments
came to similar conclusions regarding increased risks it would be
inconceivable that lindane would be registered. The EFED assessment
simply does not support the registration of lindane.
Minor
Corrections
1.
endocrine
effects in fish not cited in the EFED risk assessment:
Exposure to 0.05 mg/L (50 ppb) lindane has been found to
impact carbohydrate metabolism in rainbow trout (Oncorhynchus mykiss) by increasing plasma glucose levels and mobilizing glycogen stores
along with altering other aspects of carbohydrate metabolism (Soengas,1997)
. Also in
rainbow trout (sac-fry), 1 mg lindane /L (1 ppm) was found to cause
rapid liver glycogen depletion along with other effects on liver
ultrastructure (Sylvie,1996)
.
Lindane has been found to significantly decrease
testosterone, 17b
estradiol, estrone, and 17a-hydroxyprogesterone levels in female freshwater catfish (Heteropneustes
fossilis)
at doses of 4 ppm and
16 ppm (4 and 16 mg/l for 4 weeks) during multiple phases of the
reproductive cycle (preparatory, prespawning, spawning, postspawning
(testostosterone only), resting phase (testosterone only) (Singh,1992)
. Similarly,
lindane has been found to decrease gonadosomatic index (GSI) and
gonadotropin in male (at 0.1 ppm) and female (at 0.01 ppm) goldfish
(Carassius auratus) (Singh,1994)
. In vitro studies with goldfish gonads found decreased
testosterone and testosterone glucuronide production, altered
11-deoxycortisol production (direction of effect depended on dose
and sex), and increased 11-deoxycortisol glucuronide production in
both sexes (Singh,1994)
.
2.
Appendix
II; ii Freshwater invertebrates chronic RQ calculation:
The chronic RQ uses a daphnia NOAEC of 54 ppb.
We suggest reducing the NOAEC to at least 6.9 mg/l (ppb) based on reproductive effects in H.
azteca described on page 13 of the draft assessment.
But furthermore, lindane has been found to decrease
freshwater plankton (Copepode
nauplii)
density at levels of 6.4 mg/l
or 6.4 ppb (measured concentration) resulting in a NOAEC of 3.2 mg/l.
In this case the authors identify 6.4 mg/l as the LOAEC, but examination of Figure 2 also appears to
reveal decreased population density at the end of the 2 week
exposure to 3.2 mg lindane/l (Fliedner,1996)
.
In summary, we believe the narrow scope of the
draft assessment (ignoring exposure to a-HCH
and b-HCH
isomers, pharmacological exposure, past use residues, breast milk
exposure, dietary exposure via fish) and the potential risk to
wildlife, including endangered species, resulting from lindane seed
treatments do not support lindane registration. Should EPA
nevertheless opt to register lindane, it should retain the 10X
safety factor.
We appreciate the opportunity to provide these
comments in response to the lindane preliminary draft assessment.
Sincerely,
Kristina Thayer, PhD
Theo Colborn, PhD
Program Scientist
Senior Program Scientist and Director
Wildlife and Contaminants Program
Wildlife and Contaminants Program
(202) 822-3473
(202) 778-9643
kristina.thayer@wwfus.org
Sarah Lynch, PhD
Center for
Conservation Innovation
(202) 778-9781
lynch@wwfus.org
Documentation
TABLE 1.
Comparison of Pre- and Post-1996 Multigenerational Study
Guidelines
|
pre-1996
|
post-1996
|
F0
pre-breed exposure
·
no vaginal smears specified
|
F0
pre-breed exposure
·
estrous cyclicity
|
F1
and F2 weaning necropsy
·
organ
weights not specified
|
F1
and F2 weaning necropsy
·
special
attention to reproductive organs, organ weights of brain,
liver, thymus
·
retain
gross lesions and target organs
|
F1
pre-breed exposure
·
no
vaginal smears specified
·
no
measures of sexual maturity specified
|
F1
pre-breed exposure
·
age
of vaginal patency
·
preputial
separation
·
estrous
cyclicity
|
F0
and F1 parental necropsy
·
organ
weights not specified
·
reproductive
organs retained for histopathology
|
F0
and F1 parental necropsy
·
gross
necropsy; special attention to reproductive organs
·
absolute
and relative organ weights:
uterus, ovaries, testes, epididymides (total and
cauda), prostate, seminal vesicles (with coagulating glands
and their fluids), brain, liver, kidney, adrenal glands,
spleen, known target organs
·
retained
for histopathology:
vagina, uterus with cervix, ovaries with oviducts,
testes, epididymides, prostate, seminal vesicles, coagulating
glands, known target organs and gross lesions
|
F0
and F1 male reproductive assessment
·
no
sperm assessments specified
·
no
spermatid head counts specified
·
no
details of examination of testis and epididymides
|
F0
and F1 male reproductive assessment
·
cauda
epididymides (or vas deferens for motility and morphology),
sperm number, sperm motility, sperm morphology, testes
(homogenization resistant spermatids)
·
retained
for histopathology:
testis
– atrophy, tumors, retained spermatids, missing germ cell
layers or types, multinucleated giant cells, sloughing off of
spermatogenic cells into lumen
epididymis
– caput corpus, longitudinal section, sperm granulomas,
leukocyte infiltration (inflammation), aberrant cell types in
lumen, absence of clear cells in cauda epithelium
|
F0
and F1 female reproductive assessment
·
stages
of estrous at necropsy not specified
·
no
details of examination of ovaries
|
F0
and F1 female reproductive assessment
·
vaginal
smears for estrous cyclicity
·
identification
of estrous at time of termination
·
post-lactational
ovary
– five ovarian sections should be taken at least 100mm
apart from inner third of each ovary, total number of
primordial follicles from those 10 sections, presence or
absence of growing follicles and corpora lutea
|
Triggers
·
AGD
of F2 newborns not specified
·
histopathology
of weanling organs not specified
·
histopathology
of reproductive organs based on estrous cyclicity or sperm
measures not specified
|
Triggers
·
if
treatment-related effects on F1 sex ratio or sexual
maturation, AGD measured in F2 offspring on PND 0
·
histopathology
of gross lesions; if effects observed in high dose animals,
histopathology of target organs in mid or low dose levels
·
if
treatment-related effects are observed in fertility, cyclicity
or sperm measures, histopathology of reproductive organs in
low and mid dose animals
·
if
treatment-related effects observed in gross pathology or organ
weight data, histology of weanling organs
|
|
| 5/10/99
DRAFT
THE OFFICE OF PESTICIDE PROGRAMS’ POLICY
ON
DETERMINATION OF THE APPROPRIATE FQPA SAFETY FACTOR(S)
FOR USE IN THE TOLERANCE-SETTING PROCESS
OFFICE OF PESTICIDE PROGRAMS
U.S. ENVIRONMENTAL PROTECTION AGENCY
MAY, 1999
1
TABLE OF CONTENTS
I. EXECUTIVE SUMMARY
II. PURPOSE OF THIS DOCUMENT AND INTRODUCTION
III. LEGAL FRAMEWORK
A. Statutory Provision on the FQPA 10X Safety Factor
B. Key Interpretational Issues
1. Is There a Difference Between a Safety Factor and an Uncertainty
Factor?
2. What is the FQPA Safety Factor Additional To?
3. What Additional Factors Qualify as FQPA Safety Factors?
4. What Discretion Does EPA Have in the Application of the Additional
FQPA Safety Factor?
5. What Are Reliable Data?
IV. OVERALL APPROACH TO THE FQPA SAFETY FACTOR
A. The Default 10X Safety Factor vs. A Different Safety Factor
B. The Problem of Double-Counting
C. The Process for Decision-making on the FQPA Safety Factor
D. Core Elements of OPP’s Policy on the FQPA Safety Factor
1. Pesticides Covered by the FQPA Safety Factor
2. Population Subgroups Covered by the FQPA Safety Factor
2
3. New Policy Directions
a. Potential Pre- and Postnatal Toxicity
b. New Data Requirements
V. CONSIDERATIONS RELATED TO THE UNDERSTANDING OF THE HAZARD
POTENTIAL IN THE ASSESSMENT OF RISK TO INFANTS AND CHILDREN
A. Accounting for the Completeness of the Toxicology Database and Application of
the Database Uncertainty Factor
1. Past OPP Policy and Practice with Respect to the FQPA Safety Factor and
the Completeness of the Toxicology Database
a. Hazard Identification
b. The Use of Uncertainty Factors in Dose Response Assessments
2. The Recommendations of the Toxicology Workgroup of the Agency 10X
Task Force
a. Data Requirements
b. The Use of Uncertainty Factors in Dose Response Assessments
3. The OPP Policy with Respect to the Completeness of the Toxicology
Database, the Database Uncertainty Factor and the FQPA Safety
Factor
a. Data Requirements
b. The Use of Uncertainty Factors in Dose Response Assessments
c. Evaluation of the FQPA Safety Factor for Certain Newly-required
Studies Prior to Their Inclusion in the Core Toxicology
Database
B. Determination of the Degree of Concern for Potential Pre- and Postnatal Effects
on Infants and Children
1. Past OPP Policy and Practice with Respect to the FQPA Safety Factor
and the Potential for Pre- and Postnatal Toxicity
3
2. The Recommendations of the Toxicology Working Group of the Agency
10X Task Force
3. The OPP Policy with Respect to the Degree of Concern for Potential Pre-
and Postnatal Toxicity
VI. CONSIDERATIONS RELATED TO THE UNDERSTANDING OF THE EXPOSURE
POTENTIAL IN THE ASSESSMENT FOR RISK TO INFANTS AND CHILDREN
A. What Constitutes a Complete and Reliable Exposure Database for a Food-use
Pesticide When Assessing Aggregate Risk to Infants and Children?
1. Dietary
a. Food
b. Drinking Water
2. Residential and Other Non-occupational Exposures
B. How the Approaches for Assessing Single Exposure Pathways
(Food, Drinking Water, and Residential and Other Non-occupational
Exposures) Compensate for Database Deficiencies in the Understanding the
Potential for Exposure to Infants and Children via Each of These Pathways
1. Dietary
a. Food
b. Drinking Water
2. Residential and Other Non-occupational Exposures
C. How the Proposed Approach for Assessing Aggregate Exposures Compensates
for Exposure Database Deficiencies in the Understanding the Potential for
Exposure to Infants and Children
VII. INTEGRATION OF THE STATUTORY REQUIREMENTS WITH THE CURRENT
RISK ASSESSMENT PROCESS
A. Principles for Integrating the FQPA Safety Factor with the Current Risk
Assessment Process
4
B. Scope of the FQPA Safety Factor Analysis
VIII. REFERENCES
5
DETERMINATION OF THE APPROPRIATE FQPA SAFETY FACTOR(S)
FOR USE IN THE TOLERANCE-SETTING PROCESS
I. EXECUTIVE SUMMARY
On August 3, 1996, the Food Quality Protection Act of 1996 (FQPA) was signed into
law. Effective on signature, FQPA significantly amended the Federal Insecticide, Fungicide, and
Rodenticide Act (FIFRA) and the Federal Food, Drug, and Cosmetic Act (FFDCA). Among
other changes, FQPA established a stringent health-based standard (“a reasonable certainty of no
harm”) for pesticide residues in food to assure protection from unacceptable pesticide exposures.
The new law also provided heightened protections for infants and children. Specifically, it
directed EPA to use an additional tenfold margin of safety in assessing the risks to infants and
children, to take into account the potential for pre- and postnatal toxicity and the completeness of
the toxicology and exposure databases. The statute authorized EPA to replace this default 10X
“FQPA Safety Factor” with a different factor only if, based on reliable data, the resulting margin
would be safe for infants and children.
Because of the critical importance of assuring adequate protection of infants and children,
EPA established an intra-agency Task Force of senior staff, knowledgeable in the fields of hazard
and exposure assessment, to identify the types of information that would be appropriate for
evaluating the safety of pesticides to infants and children. The Task Force included
representatives from the Office of Prevention, Pesticides and Toxic Substances, the Office of
Research and Development, the Office of Children’s Health Protection, the Office of Water, and
the Office of Solid Waste and Emergency Response. The two Task Force reports contained many
useful recommendations considered by the Office of Pesticide Programs in the development of
this guidance document.
This document describes the Office of Pesticide Programs’ (OPP) policies for determining
the appropriate Food Quality Protection Act (FQPA) Safety Factor(s) to apply when establishing,
modifying, leaving in effect or revoking a tolerance or exemption for a food use pesticide. It
presents the legal framework for the FQPA Safety Factor and key interpretations of that
framework. It states that, while the legislative language incorporates the term “safety factor”
instead of the term “uncertainty factor,” OPP believes that Congress clearly intended the FQPA
Safety Factor to address uncertainty resulting from incompleteness of data and, therefore, deems
the statutory term to incorporate the “uncertainty factor” concept. The document offers the
opinion that the FQPA Safety Factor is to be applied in addition to the two routine or baseline
uncertainty factors which account for 1) differences in sensitivity and variability between humans
(the “intraspecies” uncertainty factor) and 2) differences in sensitivity between experimental
animals and humans, if animal data have been used as the basis for deriving the hazard values (the
“interspecies” uncertainty factor). Therefore, the FQPA Safety Factor would include other
uncertainty or modifying factors used in the calculation of hazard values, for example, the
database uncertainty factor that is applied when one or more critical core studies are missing.
6
The document describes the universe of pesticides for which FQPA Safety Factor determinations
would be made primarily as food-use chemicals of “conventional” chemistry for which hazard
values such as the acute or chronic reference doses (RfD) can be derived. OPP would expect to
make FQPA Safety Factor decisions when assessing risk to infants and children up through the
time of sexual maturation, women of child-bearing age, and on occasion, sexually mature males.
FQPA Safety Factor recommendations will occur as the risk characterization is being developed;
the final decision will be made during the risk management process. .
The guidance describes the criteria by which OPP determines the completeness of the
toxicology database for conducting a high quality hazard characterization. OPP makes this
determination employing a weight-of-the-evidence (WOE) approach. The core toxicology
database for a specific chemical generally consists of studies which meet three criteria: 1) All
studies in the core database must have “official” testing guidelines or standard, well-documented
protocols available; 2) They will have been required under FIFRA/ FFDCA as first tier
requirements or triggered by the results of Tier 1 or other existing studies (see the regulations in
40 CFR 158.340 “Subpart F”) or under a well-established policy and practice for registration and
reregistration/renewal (e.g., data call-ins) and this requirement has resulted in the generation and
submission of the data with which the Agency has acquired experience in evaluating; and, 3)
There is consensus in the scientific community that there is a body of evidence supporting the
conclusion that the results of such studies improve in a significant way the understanding of the
potential hazard of the pesticide to humans, including infants and children.
The document notes that OPP will, in the next few months, propose to revise the
toxicology data requirements in Part 158, to include several new studies as Tier 1 requirements
(e.g., the acute and subchronic neurotoxicity studies in adult mammals, the developmental
neurotoxicity study, two immunotoxicity studies, and the 21-day dermal study) plus others as Tier
2 (i.e., conditionally required). In addition, there is a description of the criteria and other bases by
which OPP has concluded that it is appropriate to begin the process to issue data call-ins for the
acute and subchronic neurotoxicity studies in adult mammals and the developmental neurotoxicity
study for a subset of conventional chemistry pesticides which are known neurotoxins.
The practice of application of a database uncertainty factor when critical core studies are
missing or inadequate is described, including the expectation that the number of studies
considered critical for a “high confidence” chronic reference dose will be expanded in the near
term from five to six, and, then, after the studies are routinely required, received and understood,
to eight. The database uncertainty factor fulfills the same purpose as, and, in effect, becomes part
of the FQPA Safety Factor.
This guidance document incorporates the criteria and factors for assessing the degree of
concern regarding the potential for pre- and postnatal effects, as presented in the framework
described in the report of the Toxicology Working Group of the Agency 10X Task Force entitled
“Toxicology Data Requirements for Assessing Risks of Pesticide Exposure to Children’s Health.”
(Toxicology Working Group, 1999).
7
It also considers the completeness of the toxicology database and degree of concern in the
selection and application of uncertainty factors when calculating the acute or chronic RfD and in
the recommendations regarding the FQPA Safety Factor. The RfD derivation process takes into
account deficiencies in the core toxicology database and the potential for hazard to fetuses, infants
and children (and, therefore, the degree of concern). This paper articulates criteria for
determining OPP’s overall level of confidence in the hazard-related information and hazard
assessment approaches employed. If, for some reason, an assessment does not meet this standard,
then the assessment is said to contain “residual uncertainties or concerns.” Any residual concerns
remaining after the hazard assessment is examined are dealt with when making the final FQPA
Safety Factor decision(s). During the period after a determination is made to require new
toxicology studies, but before they become part of the core toxicology database, their absence is
evaluated as part of “residual uncertainties or concern” in the FQPA Safety Factor assessment
process. This document states OPP’s intention to solicit broad public input regarding the
appropriate consideration of the absence of these particular newly-required studies in the FQPA
Safety Factor assessment process.
Just as for hazard potential, determination of the completeness of the exposure databasein
the context of aggregate exposure and risk assessment-is a primary consideration relative to the
FQPA Safety Factor. As described in the report of the Exposure Working Group of the Agency
10X Task Force entitled “Exposure Data Requirements for Assessing Risks of Pesticide Exposure
to Children’s Health” (Exposure Working Group, 1999), OPP estimates exposure using chemicalspecific
and other reliable empirical data as well as models and conservative assumptions, which
also are based upon reliable data. The Office is confident that, in the great majority of cases, it is
not underestimating exposure to infants and children or to the general population. The guidance
document acknowledges the desirability of obtaining more extensive and specific exposure data
and notes that OPP continues to pursue the acquisition of such data from the private sector and its
own and other agencies’ research efforts. If any residual concerns remain after the exposure
assessment is examined, these are dealt with when making the final FQPA Safety Factor
decision(s). The guidance states that the absence of detailed and specific exposure data would
require the application of an additional safety factor unless OPP can determine that the available
data and its assessment methodologies give a high degree of confidence that exposure to infants
and children is not underestimated. However, because OPP’s approach to estimating exposure
in the absence of extensive, specific data is typically very conservative, OPP can usually conclude,
with a high degree of confidence, that its approach adequately protects infants and children, and
the FQPA Safety Factor would not be needed to address uncertainties in the exposure database.
8
The guidance document notes that the
decision, either that the default FQPA
Safety Factor is to be applied or that
there are reliable data which support
the application of a different factor,
uses a “weight-of-the-evidence”
(WOE) approach. This approach
simply means that all of the data with
regard to both hazard and exposure
are considered simultaneously as the
total body of evidence with regard to
the pesticide(s) being evaluated. The
integration approach to evaluating the
available hazard- and exposurerelated
information involves
characterization of the overall
confidence that infants and children
will be protected. As illustrated in the
figure, the weight-of-the-evidence
considerations include the level of
confidence in the hazard and exposure
assessments, and whether or not there
are any residual uncertainties
identified in the risk characterization.
If there is a high level of confidence
that the combination of the hazard and
exposure assessments is adequately
protective of infants and children, then
the default FQPA factor would not be
applied at this stage in the process.
For example, the optimal case would
be one in which there is a high level of confidence that the hazard and exposure assessments are
sufficiently conservative and there are no residual uncertainties in the assessment; then it would
not be necessary to apply an additional safety factor to protect infants and children. At the other
extreme is the case where OPP may find that reliable data do not support a particular finding
other than to retain the 10X default factor, given the low level of confidence that the hazard and
exposure assessments are sufficiently conservative and there are residual uncertainties that have
not been dealt with in the assessment. Alternatively, in other cases where there is also a low level
of confidence in the hazard and exposure assessments and residual concerns remain, an additional
safety factor other than the 10X default (perhaps even greater) would be applied. The size of the
final factor would depend on the overall weight-of- the-evidence and the level of confidence in the
assessment.
9
The recommendation concerning the FQPA factor is made based upon consideration of the nature
and level of confidence in the hazard and exposure assessments, the degree of concern for
potential hazard to the fetus, infants and children, and any residual uncertainties that are not
accounted for in the hazard and exposure assessments. The final decision on the FQPA Factor is
informed by the science presented in the risk characterization and the recommendation.
II. PURPOSE OF THIS DOCUMENT AND INTRODUCTION
The purpose of this document is to describe the policies employed by the Office of
Pesticide Programs in making a determination regarding the FQPA Safety Factor when
developing aggregate risk assessments and regulatory decisions for single active ingredient
pesticides. In the future, as the approaches for conducting cumulative risk assessments are
developed and applied, this document may require modification and updating to articulate the
policies attendant to the FQPA Safety Factor in the assessment and regulation of groups of
chemicals sharing a common mechanism of toxicity.
This version of the policy has been written in light of review and comment offered by the
FIFRA Scientific Advisory Panel (SAP) on several earlier versions over the last two and a half
years, comments by other external parties offered in the context of these SAP meetings, and the
reports of the Toxicology and Exposure Working Groups of the Agency 10X Task Force. The
Agency 10X Task Force was established in March, 1998, to assist in addressing the general
considerations regarding the use of the ten-fold margin of safety for infants and children provided
for in the FQPA. The Task Force formed a Toxicology Working Group and an Exposure
Working Group. Working Group members included representatives from EPA’s Offices of
Prevention, Pesticides and Toxic Substances, Research and Development, and Children’s Health
Protection as well as other Agency offices with an interest in the issue. A representative from the
U.S. Department of Agriculture participated in the Exposure Working Group.
The approach set forth in this document will be subjected to public notice and comment in
accordance with the processes suggested by the Tolerance Reassessment Advisory Committee. It
also will be discussed at the May, 1999, meeting of the FIFRA Scientific Advisory Panel. The
guidance document then will be revised, as appropriate, and issued later this year.
III. LEGAL FRAMEWORK
A. Statutory Provision on the FQPA Safety Factor
The Food Quality Protection Act (FQPA) of 1996 (Pub. L.104-170) was signed into law
on August 3, 1996. FQPA establishes a new safety standard and new procedures for EPA’s
pesticide tolerance-setting activities. Under new Section 408(b)(2)(A)(i) of FFDCA, EPA can
establish, revise or leave in effect a tolerance (the legal limit for a pesticide chemical residue in or
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on a food) only if it is determined to be "safe." Section 408(b)(2)(A)(ii) defines "safe" to mean
that "there is a reasonable certainty that no harm will result from aggregate exposure to the
pesticide chemical residue, including all anticipated dietary exposures and all other exposures for
which there is reliable information." Section 408(b)(2)(C) requires EPA to give special
consideration to infants and children by ensuring “that there is a reasonable certainty that no harm
will result to infants and children from aggregate exposure to the pesticide chemical residue."
The FQPA instructs EPA, in making its “reasonable certainty of no harm” finding, that in
“the case of threshold effects,...an additional tenfold margin of safety for the pesticide chemical
residue and other sources of exposure shall be applied for infants and children to take into account
potential pre- and postnatal toxicity and completeness of data with respect to exposure and
toxicity to infants and children.” Section 408 (b)(2)(c) further states that “the Administrator may
use a different margin of safety for the pesticide chemical residue only if, on the basis of reliable
data, such margin will be safe for infants and children.”
Threshold effects are those considered to have exposure doses at some identifiable level
which are likely to be without appreciable risk of deleterious consequences. The shapes of the
dose response curves for such effects would be expected to be non-linear. Both cancer and noncancer
effects may exhibit these properties.
(FQPA contains terms related to risk assessment that are outdated or inconsistent with the
Agency’s and OPP’s current risk assessment vocabulary and practices. This document will use
language that reflects current practice. For instance, the term “hazard” will be used instead of
“toxicity” when used in combination with “assessment” or “characterization” to describe those
phases of the risk assessment process.)
B. Key Interpretational Issues
1. Is there a difference between a safety factor and an uncertainty factor?
When regulatory agencies first adopted the approach of setting acceptable levels of
exposure to potentially risky substances, those levels were usually derived by dividing the dose
levels at which no adverse effects were seen in animal studies by “safety factors” designed to
account for, among other things, differences between animals and humans and differences among
humans (commonly referred to as the inter- and intraspecies factors). Because the factors cannot
guarantee absolute safety and the factors are an attempt to address uncertainties in the knowledge
base, more recently, EPA has begun using the term “uncertainty factors” instead of “safety
factors.”1 Given that EPA has used both terms to address the same concept and Congress clearly
1 EPA also uses the term “modifying factor” to describe another factor sometimes used in
the derivation of the RfD. The “modifying factor,” as EPA employs it, is applied when scientific
uncertainties in the study chosen for derivation of the RfD are not explicitly addressed by one or
more of the “uncertainty factors.” OPP does not regard Congress’ use of the term “safety factor”
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intended the FQPA factor to cover uncertainty resulting from incompleteness of data, OPP does
not read any substantive meaning into Congress’ use of the phrase “safety factor” rather than
“uncertainty factor.” The equivalence in the use of the terms “safety factor” and “uncertainty
factor” is further reflected in the legislative history where Congress both described the traditional
inter- and intraspecies factors as “safety factors” and directed that the FQPA Safety Factor
provision be interpreted in furtherance of the NRC/NAS recommendation for use of an additional
“uncertainty factor” of up to 10X to protect infants and children (House report 104-669, 104th
Congress, 2d Sess. 41, 43 (1996)).
Even though EPA more frequently uses the term “uncertainty factor,” because the statute
uses the term “safety factor,” OPP will continue to use the term “safety factor” in referring to the
additional FQPA factor for the protection of infants and children. Nevertheless, because this
document discusses past OPP actions and Agency-wide policies, OPP often will also use the term
“uncertainty factor” in this document.
2. What is the FQPA Safety Factor additional to?
Congress specified that the 10X factor should be an “additional” factor without stating in
the statute what served as the baseline safety factor. Nonetheless, given existing risk assessment
procedures, there can be little doubt as to Congress’ intention. For almost 30 years, EPA, as well
as others in the scientific and regulatory community, has routinely been using at least two ten-fold
safety or uncertainty factors when relying on animal testing to assess the potential for human
hazard posed by exposure to chemicals. The two ten-fold factors used most often are designed to
address both the extrapolation of the results of animal studies to humans and variability and
sensitivity within humans and to serve as the starting point for defining an acceptable exposure
level for a chemical. Furthermore, it is also well-established regulatory practice to apply, on a
case-by-case basis, “additional” safety, uncertainty, or modifying factors along with the baseline
inter- and intra-species factors where the circumstances warrant such additional factors. These
additional factors have been used principally to address gaps in the toxicology database or
deficiencies in the key existing toxicology studies. For food use pesticides, it only infrequently has
been found to be necessary to apply additional factors to account for gaps or deficiencies of this
nature. OPP has traditionally not used safety or uncertainty factors to address exposure issues.
Thus, consistent with OPP’s past risk assessment and regulatory practices, OPP believes Congress
intended that the additional FQPA Safety Factor be “in addition to” only the standard, baseline
inter- and intra-species uncertainty factors.
3. What additional factors qualify as FQPA Safety Factors?
Not only does OPP’s prior practice regarding use of the inter- and intra-species
uncertainty factors provide the baseline to which the FQPA factor is added, but OPP’s pre-FQPA
use of additional uncertainty factors helps to provide content to the FQPA Safety Factor itself. It
as excluding the concept covered by the modifying factor.
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is OPP’s view that the additional FQPA Safety Factor codified, to a certain extent, OPP’s pre-
FQPA use of uncertainty factors in addition to the standard inter- and intra-species factors. For
example, as noted, additional uncertainty or modifying factors have traditionally been used by
OPP (and EPA) to address deficiencies in the toxicology database. This concept is reflected
expressly in the FQPA Safety Factor provision by the direction that an additional 10X factor be
applied, for among other reasons, “to take into account . . . completeness of the data with respect
to . . . toxicity.” Thus, it is clear that the pre-FQPA additional uncertainty factor to address a
deficiency in the database concerning effects of concern for infants and children has become, after
passage of the FQPA, an additional FQPA Safety Factor. OPP believes it is unreasonable to
assume that when Congress specified an “additional” safety factor “to take into account . . .
completeness of the data with respect to . . . toxicity” it intended that OPP apply its traditional
database uncertainty factor where a study was missing or inadequate and then apply a second
safety factor under the FQPA for the same deficiency.
The FQPA Safety Factor provision, however, was not simply a codification of existing
practice. It was both a codification and an expansion. Prior to the enactment of the FQPA, OPP
already considered both the observed adverse effects shown in studies and the completeness of the
toxicology database in determining the appropriate composite uncertainty factor to be applied in
calculating the RfD. It was only on rare occasions, however, that OPP found that an additional
factor was needed because either the adverse effects were so severe or other substantive results
raised sufficient questions regarding the adequacy of the traditional uncertainty factors.2
Congress, by specifically including a reference to potential pre- and postnatal toxicity as a factor
justifying an additional 10X factor for pesticides, has effectively expanded OPP’s pre-FQPA
practice concerning the role substantive study results play in safety factor determination by
placing increased emphasis on potential pre- and postnatal toxicity. (An explanation of how OPP
will account for pre- and postnatal toxicity in the hazard and risk characterization phases of risk
assessment will be discussed in Section V.)
An additional expansion of pre-FQPA practice was effected by Congressional reference to
the completeness of the exposure database. Prior to the enactment of FQPA, OPP did not use an
express safety/uncertainty factor approach with exposure assessments. That is, OPP did not
modify exposure assessments by some factor to address inadequacies in the exposure database.
Rather, OPP attempted to ensure that exposure was not underestimated by using reasonable highend
exposure assumptions where empirical exposure information was unavailable. As with preand
postnatal toxicity, Congress, by explicitly referencing the completeness of the exposure
database as one of the considerations justifying an additional 10X factor, has placed new emphasis
on the need to ensure that exposure assessments are based upon complete information relevant to
infants and children so that risks are not underestimated. (An explanation of how OPP will
2 Contrary to statements in the NRC Report entitled “Pesticides in the Diets of Infants
and Children” (NRC,1993) (p.361), an additional 10X factor has not been automatically applied
by OPP or EPA whenever a study identified fetal developmental effects.
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account for completeness of the exposure database in the exposure assessment and risk
characterization phases of risk assessment is discussed in Section VI.)
. 4. What Discretion Does EPA Have in the Application of the Additional
FQPA Safety Factor?
The statute established a default position that OPP should apply an additional 10X safety
factor as a default to account for pre- and postnatal toxicity and completeness of the toxicology
and exposure databases. The statute also grants OPP the discretion to apply a different safety
factor where reliable data show that such a factor will be safe for infants and children. Thus, OPP
can either rely on the default 10X value or, in appropriate circumstances, determine that the data
support a “different” factor that is protective of infants and children. When OPP finds that it has
reliable data to set a different factor, OPP will base such different factor upon an in-depth analysis
of the underlying databases and not some sort of arbitrary dividing-up of the 10X default value.
OPP does not believe that Congress intended that the default 10X factor be split up using some
mathematical formula between pre- and postnatal toxicity and the completeness of the toxicology
and exposure databases. The in-depth analysis may result in a finding that a factor either greater
or lesser than 10X should be added to the traditional inter- and intraspecies factors or that no
additional factor in addition to the traditional factors is needed. It may also result in the
conclusion that an additional factor of 10X is retained for the protection of infants and children
because the data support the conclusion that the default value is the appropriate value.
Earlier OPP policy statements have described decisions regarding the additional FQPA
Safety Factor as to whether to “retain, reduce, or remove” the 10X factor. This language was
originally adopted by OPP to emphasize its position that the starting point in any assessment is
that the FQPA 10X Safety Factor is assumed to be necessary to protect the safety of infants ands
children unless reliable data show otherwise. Although OPP continues to adhere to this core
principle of the FQPA Safety Factor provision , OPP has dropped the “retain, reduce or remove”
language. OPP has become concerned that this language contains an erroneous implication that
would restrict implementation of the FQPA Safety Factor provision in a manner that is most
protective of infants and children. The “retain, reduce or remove” language implies that OPP
thought any “different” additional factor applied could be no greater than 10. The statute is not
so limiting. In fact, the final safety factor could be greater than 10X.
5. What are reliable data?
OPP may use a margin of safety different from the default FQPA Safety Factor where
OPP can conclude, based on “reliable data,” that the margin chosen will protect the safety of
infants and children. Several provisions in FFDCA section 408 mention the need for reliability of
data or information. (See, e.g., §§ 408(b)(2)(A)(ii), 408(b)(2)(D)(i).) OPP does not interpret the
reliable data requirement in the infants and children’s provision as mandating that any specific
14
kind of data be available, just that the data and information that form the basis for the selection of
a different safety factor must be sufficiently sound that it could routinely rely on such information
in taking regulatory action.
In conducting both hazard and exposure assessments, OPP, at times, relies on a wide
range of assumptions and models to evaluate and supplement specific data available on the
pesticide. For example, almost all hazard assessments depend on the assumption that effects
observed in animals can be used to predict both effects in humans and the level below which those
effects are not likely to occur. Rarely does OPP have human testing data for a pesticide;
however, more generic data and information concerning the relevance of animal testing to humans
are sufficiently reliable to support these assumptions. An example in the area of exposure
assessment is OPP’s use of a tolerance value as the assumed level of pesticide residue in food.
Although, in a number of circumstances, OPP has studies analyzing pesticide residue levels in
food at the time of purchase or consumption by the consumer, there are many circumstances,
particularly those involving most new pesticides, where OPP does not have such data. OPP
generally does have data showing residue levels at the time of harvest, as well as more general
information regarding what happens to residue levels over time and during food processing.
Taken together, this information provides reliable data supporting OPP’s assumption that using
tolerance level values for residue levels will not understate exposure.
In examining whether empirical data used with assumptions or models provide reliable
data that allow OPP to set a different margin of safety than the additional ten-fold default value
for the protection of infants and children, OPP will focus on whether the assumption or model is
based on reasonable scientific judgment that hazard or exposure, as applicable, will not be
underestimated. To be reasonable, scientific judgment may not be based on mere speculation but
must take into account relevant information and data. How much information and data, and how
specific those data must be, will depend on the nature of the assumption. In some cases, only
very general information or data will be needed. For example, in the absence of data on dermal
absorption for a pesticide, OPP will often assume that the pesticide is one hundred percent
absorbed. If such an assumption is made, the absence of the specific dermal absorption data
would not mean that OPP does not have “reliable data” to make a finding on children’s safety.
Rather, basic scientific principles provide the reliable data to support the assumption that a human
cannot absorb more than 100 percent of a substance to which he or she is exposed dermally. OPP
can conclude that the assumption is a reasonable scientific judgment that ensures that children’s
exposure has not been underestimated for this route of exposure.
IV. OVERALL APPROACH TO THE FQPA SAFETY FACTOR
A. The Default 10X Safety Factor vs. a Different Safety Factor
As explained above, the statute established an additional 10X factor as a default value or
but also gives OPP the discretion to apply a different margin of safety based on reliable data and
an individualized assessment, on a case-by-case basis. FQPA requires that an additional 10X
15
factor be applied as a default where it cannot be shown on the basis of reliable hazard and
exposure information and assessments that a different safety factor would maintain an adequate
margin of safety for infants and children. Where reliable data are available, however, OPP has the
discretion to choose between the default approach and an individualized assessment. OPP, as a
policy matter, prefers not to simply apply a default value in making decisions under section 408
where reliable data are available that support an individualized determination. In OPP’s view, the
statute’s prescription for use of a default additional 10X safety factor to address such varied, and
potentially serious, concerns as potential pre- and postnatal toxicity, and the completeness of the
toxicology and exposure databases is somewhat of a crude instrument. A pesticide may have
weaknesses in its toxicology and exposure databases but indicate no concern for potential pre- or
postnatal toxicity. Another pesticide might have a complete database that demonstrates that it
does result in pre-natal toxicity. A third pesticide might have an incomplete database that,
nonetheless, shows the potential for pre- and postnatal toxicity. Further, incomplete databases are
not equally incomplete, and all pre- or postnatal toxicities are not of equal concern. Yet, if the
10X factor is applied as a default, each of these myriad variations would get exactly the same
treatment. A 10X factor might overprotect in one instance but underprotect in the next. For
example, prior to the passage of the FQPA, deficiencies in the hazard data alone, on occasion,
prompted OPP to apply one or more additional factors of up to 10X.3 Conversely, where data
deficiencies are minor and any pre- or postnatal toxicity identified is well characterized, use of an
additional 10X factor may be unnecessary to protect infants and children.
For these reasons, where reliable data are available, OPP favors an approach that attempts
to make a specific case-by-case determination as to the size of the additional factor rather than
rely on the 10X default value. Determination of the magnitude of the additional factor would
involve evaluating the completeness of the toxicology and exposure databases and the potential
for pre- or postnatal toxicity. OPP believes that careful analysis of the completeness and quality
of the existing databases should, in most instances, account for uncertainties including FQPA
considerations such that OPP will not have to rely on the additional 10X value as a default.
Individualized assessments may still result in the use of an “additional” factor of 10X.
Alternatively, these assessments may result in “additional” factors greater or less than 10X, or no
additional factor at all.
B. The Problem of Double-Counting `
Certainly, the major focus of application of the statutory provision on the FQPA Safety
Factor is to insure that infants and children are adequately protected from unsafe risks to
conventional food-use pesticides. Nonetheless, care must be taken to avoid the “double-
3 These uncertainty factors cover three areas of deficiency: lack of good long-term dosing
data, lack of a “good” NOAEL, and lack of other key data in the database needed to yield a high
confidence hazard value (e.g., RfD). In addition, on one occasion, OPP incorporated an
additional factor because the animal hazard data indicated a very high degree of concern for
human health. [See further discussion below]
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counting” of safety/uncertainty factors. Such double-counting could occur in one of two ways.
First, given that the determination of the FQPA Safety Factor builds upon prior practice with
regard to the application of additional uncertainty factors in the risk assessment process, doublecounting
could occur if the same concern was relied upon to justify both a traditional uncertainty
factor and a separate FQPA Safety Factor. For example, when calculating an RfD, OPP may
apply a database uncertainty factor where a key core study addressing potential hazard to infants
and children is missing or inadequate. To apply a second uncertainty factor, under the aegis of the
FQPA Safety Factor, to address the same completeness of data issue would be an unjustified
doubling of additional safety/uncertainty factors. OPP believes that by making clear in this
document that traditional additional uncertainty factors, s | |
