Dichlorvos (DDVP); Order Denying NRDC's Objections and Requests for Hearing, 42683-42713 [E8-16617]

Agencies

• ENVIRONMENTAL PROTECTION AGENCY

[Federal Register Volume 73, Number 142 (Wednesday, July 23, 2008)]
[Rules and Regulations]
[Pages 42683-42713]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: E8-16617]


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ENVIRONMENTAL PROTECTION AGENCY

40 CFR Part 180

[EPA-HQ-OPP-2002-0302; FRL-8372-5]


Dichlorvos (DDVP); Order Denying NRDC's Objections and Requests 
for Hearing

AGENCY: Environmental Protection Agency (EPA).

ACTION: Final Order.

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SUMMARY: In this order, EPA denies objections to, and requests for 
hearing on, a prior order denying a petition requesting that EPA revoke 
all pesticide tolerances for dichlorvos under section 408(d) of the 
Federal Food, Drug, and Cosmetic Act. The objections and hearing 
requests were filed on February 1, 2008, by the Natural Resources 
Defense Council (``NRDC''). The Original petition was also filed by 
NRDC.

DATES: This order is effective July 23, 2008.

ADDRESSES: EPA has established a docket for this action under docket 
identification (ID) number EPA-HQ-OPP-2002-0302. To access the 
electronic docket, go to https://www.regulations.gov, and search for the 
docket number. Follow the instructions on the regulations.gov website 
to view the docket index or access available documents. All documents 
in the docket are listed in the docket index available in 
regulations.gov. Although listed in the index, some information is not 
publicly available, e.g., Confidential Business Information (CBI) or 
other information whose disclosure is restricted by statute. Certain 
other material, such as copyrighted material, is not placed on the 
Internet and will be publicly available only in hard copy form. 
Publicly available docket materials are available in the electronic 
docket at https://www.regulations.gov, or, if only available in hard 
copy, at the OPP Regulatory Public Docket in Rm. S-4400, One Potomac 
Yard (South Bldg.), 2777 S. Crystal Dr., Arlington, VA. The Docket 
Facility is open from 8:30 a.m. to 4 p.m., Monday through Friday, 
excluding legal holidays. The Docket Facility telephone number is (703) 
305-5805.

FOR FURTHER INFORMATION CONTACT: Susan Bartow, Special Review and 
Reregistration Division (7508P), Office of Pesticide Programs, 
Environmental Protection Agency, 1200 Pennsylvania Ave., NW., 
Washington, DC 20460-0001; telephone number: 703-603-0065; e-mail 
address: bartow.susan@epa.gov.

SUPPLEMENTARY INFORMATION:

I. General Information

A. Does this Action Apply to Me?

    In this document EPA denies objections and hearing requests by the 
Natural Resources Defense Council (``NRDC'') concerning EPA's denial of 
NRDC's petition to revoke pesticide tolerances. This action may also be 
of interest to agricultural producers, food manufacturers, or pesticide 
manufacturers. Potentially affected entities may include, but are not 
limited to those engaged in the following activities:
     Crop production (North American Industrial Classification 
System (``NAICS'') code 111), e.g., agricultural workers; greenhouse, 
nursery, and floriculture workers; farmers.
     Animal production (NAICS code 112), e.g., cattle ranchers 
and farmers, dairy cattle farmers, livestock farmers.
     Food manufacturing (NAICS code 311), e.g., agricultural 
workers; farmers; greenhouse, nursery, and floriculture workers; 
ranchers; pesticide applicators.
     Pesticide manufacturing (NAICS code 32532), e.g., 
agricultural workers; commercial applicators; farmers; greenhouse, 
nursery, and floriculture workers; residential users.
    This listing is not intended to be exhaustive, but rather to 
provide a guide for readers regarding entities likely to be affected by 
this action. Other types of entities not listed in this unit could also 
be affected. The NAICS codes have been provided to assist you and 
others in determining whether this action might apply to certain 
entities. If you have any questions regarding the applicability of this 
action to a particular entity, consult the person listed under FOR 
FURTHER INFORMATION CONTACT.

B. How Can I Access Electronic Copies of this Document?

    In addition to accessing an electronic copy of this Federal 
Register document through the electronic docket at https://
www.regulations.gov, you may access this Federal Register document 
electronically through the EPA Internet under the ``Federal Register'' 
listings at https://www.epa.gov/fedrgstr. You may also access a 
frequently updated electronic version of EPA's tolerance regulations at 
40 CFR part 180 through the Government Printing Office's pilot e-CFR 
site at https://www.gpoaccess.gov/ecfr.

C. Acronyms

    The following is a list of acronyms used in this order:
CSFII - Continuing Survey of Food Intakes by Individuals
CNS - Central Nervous System
DDVP - dichlorvos
EDSTAC - Endocrine Disruptor Screening and Testing Advisory 
Committee
EPA - Environmental Protection Agency
FACA - Federal Advisory Committee Act
FDA - Food and Drug Administration
FIFRA - Federal Insecticide, Fungicide, and Rodenticide Act
FFDCA - Federal Food, Drug, and Cosmetic Act
FQPA - Food Quality Protection Act of 1996
HSRB - Human Studies Review Board
IRED - Interim Reregistration Eligibility Decision
LOAEL - Lowest Observed Adverse Effect Level
MOE - Margin of Exposure
MRID - Master Record Identification
NOAEL - No Observed Adverse Effect Level
NRDC - Natural Resources Defense Council
OECD - Organisation for Economic Co-operation and Development
PAD - Population Adjusted Dose
ppm - parts per million
RBC - red blood cell
RED - Reregistration Eligibility Decision
RfD - Reference Dose
SDWA - Safe Drinking Water Act
SOP - Standard Operating Procedure
USDA - United Stated Department of Agriculture

II. Introduction

A. What Action Is the Agency Taking?

    In this order, EPA denies objections, and requests for a hearing on 
those objections, to an earlier EPA order, (72 FR 68662 (December 5, 
2007)), denying a petition to revoke all tolerances established for the 
pesticide dichlorvos (``DDVP'') under the Federal Food, Drug, and 
Cosmetic Act (``FFDCA''), 21 U.S.C. 346a. (Refs. 1 and 2). Both the 
objections and hearing requests, as well as the petition, were filed 
with EPA by NRDC.
    NRDC's petition, filed on June 2, 2006, pursuant to FFDCA section 
408(d)(1), asserted numerous grounds as to why the DDVP tolerances 
allegedly fail to meet the FFDCA's safety standard. This petition was 
filed as EPA was completing its reassessment of the safety of the DDVP 
tolerances pursuant to FFDCA section 408(q). (Ref. 3). In response to 
the petition, EPA undertook an extensive review of its DDVP safety 
evaluation in the tolerance reassessment decision. Based on certain 
concerns raised by NRDC, EPA determined it was necessary to incorporate 
updated data on numerous points and to adopt revised and more 
conservative assumptions, in its DDVP risk assessments. This led to 
complete revisions of both EPA's assessments of

[[Page 42684]]

dietary and residential risks from exposure to DDVP. (72 FR at 68678, 
68687-68691). Nonetheless, EPA concluded that its revised risk 
assessments demonstrated that DDVP met the FFDCA safety standard and, 
therefore, denied the petition. (Id. at 68695). EPA's denial was issued 
in the form of an order under FFDCA section 408(d)(4)(iii). (21 U.S.C. 
346a(d)(4)(iii)).
    NRDC then filed objections with EPA to the petition denial order 
and requested a hearing on its objections. These objections and hearing 
requests were filed pursuant to the procedures in the FFDCA section 
408(g)(2). (21 U.S.C. 346a(g)(2)). The objections narrowed NRDC's 
claims to two main topics - that, in assessing the risk to DDVP, EPA 
unlawfully reduced the statutory safety factor for the protection of 
infants and children and EPA unlawfully relied on a human toxicity 
study. As to these claims, NRDC largely repeats the arguments as 
presented in its petition without addressing EPA's substantial 
revisions to the DDVP risk assessment and proffers little to no 
evidence in support of its requests for a hearing. After carefully 
reviewing the objections and hearing requests, EPA has determined that 
NRDC's hearing requests do not satisfy the regulatory requirements for 
such requests and that its substantive objections are without merit. 
Therefore, EPA, in this final order, denies NRDC's objections and its 
requests for a hearing on those objections.

B. What Is the Agency's Authority for Taking This Action?

    NRDC petitioned to revoke the DDVP tolerances pursuant to the 
petition procedures in FFDCA section 408(d)(1). (21 U.S.C. 346a(d)(1)). 
Under section 408(d), EPA may respond to such a petition by either 
issuing a final or proposed rule modifying or revoking the tolerances 
or issuing an order denying the petition. (21 U.S.C. 346a(d)(4)). Here, 
EPA responded by issuing an order under section 408(d)(4)(iii) denying 
the petition. (72 FR 68622 (December 5, 2007)).
    Orders issued under section 408(d)(4)(iii) are subject to a 
statutorily-created administrative review process. (21 U.S.C. 
346a(g)(2)). Any person may file objections to a section 408(d)(4)(iii) 
order with EPA and request a hearing on those objections. (Id.). EPA is 
required by section 408(g)(2)(C) to issue a final order resolving the 
objections to the section 408(d)(4)(iii) order. (21 U.S.C. 
346a(g)(2)(C)).

III. Statutory and Regulatory Background

    In this Unit, EPA provides background on the relevant statutes and 
regulations governing NRDC's objections and requests for hearing as 
well as on pertinent Agency policies and practices. As noted, NRDC's 
objections and requests for hearing raise two main claims: (1) that EPA 
has unlawfully failed to retain the full tenfold safety factor for the 
protection of infants and children; and (2) that it was unlawful for 
EPA to rely on a toxicity study for DDVP that was conducted with 
humans. The children's safety factor claim is based on assertions 
regarding DDVP's potential endocrine effects and the adequacy of EPA's 
data and risk assessments pertaining to exposure to DDVP in food as a 
result of the use of DDVP (and similar pesticides) in agriculture or 
food storage and through use of DDVP in residential settings. The human 
studies claim involves a challenge to the EPA regulation governing 
reliance on human studies as well as to EPA's application of that rule 
to a particular human study. The human study in question measured 
cholinesterase inhibition in humans resulting from administration of 
DDVP. Background information on each of these topics is included in 
this Unit.
    Unit III.A. summarizes the requirements and procedures in section 
408 of the FFDCA and applicable regulations pertaining to pesticide 
tolerances, including the procedures for petitioning for revocation of 
tolerances and challenging the denial of such petitions and the 
substantive standards for evaluating the safety of pesticide 
tolerances. This unit also discusses the closely-related statute under 
which EPA regulates the sale, distribution, and use of pesticides, the 
Federal Insecticide, Fungicide, and Rodenticide Act (``FIFRA''), (7 
U.S.C. 136 et seq.).
    Unit III.B. provides an overview of EPA's risk assessment process. 
It contains an explanation of how EPA identifies the hazards posed by 
pesticides, how EPA determines the level of exposure to pesticides that 
pose a concern (``level of concern''), how EPA measures human exposure 
to pesticides, and how hazard, level of concern conclusions, and human 
exposure estimates are combined to evaluate risk. Further, this unit 
presents background information on two Agency policies with particular 
relevance to this action, EPA's policy with regard to the statutory 
safety factor for the protection of infants and children and its policy 
with regard to cholinesterase inhibition.
    Unit III.C. summarizes EPA's program for implementing the statutory 
requirement to screen pesticides for potential endocrine effects. Unit 
III.D. describes the EPA regulation on use of human studies.

A. FFDCA/FIFRA and Applicable Regulations

    1. In general. EPA establishes maximum residue limits, or 
``tolerances,'' for pesticide residues in food under section 408 of the 
FFDCA. (21 U.S.C. 346a). Without such a tolerance or an exemption from 
the requirement of a tolerance, a food containing a pesticide residue 
is ``adulterated'' under section 402 of the FFDCA and may not be 
legally moved in interstate commerce. (21 U.S.C. 331, 342). Monitoring 
and enforcement of pesticide tolerances are carried out by the U.S. 
Food and Drug Administration (``FDA'') and the U.S. Department of 
Agriculture (``USDA''). Section 408 was substantially rewritten by the 
Food Quality Protection Act of 1996 (``FQPA''), which added the 
provisions discussed below establishing a detailed safety standard for 
pesticides, additional protections for infants and children, and the 
estrogenic substances screening program. (Public Law 104-170, 110 Stat. 
1489 (1996)).
    EPA also regulates pesticides under the Federal Insecticide, 
Fungicide, and Rodenticide Act (``FIFRA''), (7 U.S.C. 136 et seq). 
While the FFDCA authorizes the establishment of legal limits for 
pesticide residues in food, FIFRA requires the approval of pesticides 
prior to their sale and distribution, (7 U.S.C. 136a(a)), and 
establishes a registration regime for regulating the use of pesticides. 
FIFRA regulates pesticide use in conjunction with its registration 
scheme by requiring EPA review and approval of pesticide labels and 
specifying that use of a pesticide inconsistent with its label is a 
violation of federal law. (7 U.S.C. 136j(a)(2)(G)). In the FQPA, 
Congress integrated action under the two statutes by requiring that the 
safety standard under the FFDCA be used as a criterion in FIFRA 
registration actions as to pesticide uses which result in dietary risk 
from residues in or on food, (7 U.S.C. 136(bb)), and directing that EPA 
coordinate, to the extent practicable, revocations of tolerances with 
pesticide cancellations under FIFRA. (21 U.S.C. 346a(l)(1)).
    2. Safety standard for pesticide tolerances. A pesticide tolerance 
may only be promulgated by EPA if the tolerance is ``safe.'' (21 U.S.C. 
346a(b)(2)(A)(i)). ``Safe'' is defined by the statute to mean that 
``there is a reasonable certainty that no harm will

[[Page 42685]]

result from aggregate exposure to the pesticide chemical residue, 
including all anticipated dietary exposures and all other exposures for 
which there is reliable information.'' (21 U.S.C. 346a(b)(2)(A)(ii)). 
Section 408(b)(2)(D) directs EPA, in making a safety determination, to:
    consider, among other relevant factors- ...
    (v) available information concerning the cumulative effects of 
such residues and other substances that have a common mechanism of 
toxicity;
    (vi) available information concerning the aggregate exposure 
levels of consumers (and major identifiable subgroups of consumers) 
to the pesticide chemical residue and to other related substances, 
including dietary exposure under the tolerance and all other 
tolerances in effect for the pesticide chemical residue, and 
exposure from other non-occupational sources;
    (viii) such information as the Administrator may require on 
whether the pesticide chemical may have an effect in humans that is 
similar to an effect produced by a naturally occurring estrogen or 
other endocrine effects. ...

(21 U.S.C. 346a(b)(2)(D)(v), (vi) and (viii)).

    EPA must also consider, in evaluating the safety of tolerances, 
``safety factors which . . . are generally recognized as appropriate 
for the use of animal experimentation data.'' (21 U.S.C. 
346a(b)(2)(D)(ix).
    Risks to infants and children are given special consideration. 
Specifically, section 408(b)(2)(C) states that EPA:

    shall assess the risk of the pesticide chemical based on-- ...
    (II) available information concerning the special susceptibility 
of infants and children to the pesticide chemical residues, 
including neurological differences between infants and children and 
adults, and effects of in utero exposure to pesticide chemicals; and
    (III) available information concerning the cumulative effects on 
infants and children of such residues and other substances that have 
a common mechanism of toxicity. ...

(21 U.S.C. 346a(b)(2)(C)(i)(II) and (III)).

    This provision also creates a presumptive additional safety factor 
for the protection of infants and children. Specifically, it directs 
that ``[i]n 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 post-natal toxicity and completeness of the 
data with respect to exposure and toxicity to infants and children.'' 
(21 U.S.C. 346a(b)(2)(C)). EPA is permitted to ``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.'' 
(Id.). The additional safety margin for infants and children is 
referred to throughout this order as the ``children's safety factor.''
    3. Procedures for establishing, amending, or revoking tolerances. 
Tolerances are established, amended, or revoked by rulemaking under the 
unique procedural framework set forth in the FFDCA. Generally, a 
tolerance rulemaking is initiated by the party seeking to establish, 
amend, or revoke a tolerance by means of filing a petition with EPA. 
(See 21 U.S.C. 346a(d)(1)). EPA publishes in the Federal Register a 
notice of the petition filing and requests public comment. (21 U.S.C. 
346a(d)(3)). After reviewing the petition, and any comments received on 
it, EPA may issue a final rule establishing, amending, or revoking the 
tolerance, issue a proposed rule to do the same, or deny the petition. 
(21 U.S.C. 346a(d)(4)).
    Once EPA takes final action on the petition by either establishing, 
amending, or revoking the tolerance or denying the petition, any person 
may file objections with EPA and seek an evidentiary hearing on those 
objections. (21 U.S.C. 346a(g)(2)). Objections and hearing requests 
must be filed within 60 days. (Id.). The statute provides that EPA 
shall ``hold a public evidentiary hearing if and to the extent the 
Administrator determines that such a public hearing is necessary to 
receive factual evidence relevant to material issues of fact raised by 
the objections.'' (21 U.S.C. 346a(g)(2)(B). EPA regulations make clear 
that hearings will only be granted where it is shown that there is ``a 
genuine and substantial issue of fact,'' the requestor has identified 
evidence ``which, if established, resolve one or more of such issues in 
favor of the requestor,'' and the issue is ``determinative'' with 
regard to the relief requested. (40 CFR 178.32(b)). EPA's final order 
on the objections is subject to judicial review. (21 U.S.C. 
346a(h)(1)).
    4. Tolerance reassessment and FIFRA reregistration. The FQPA 
required that EPA reassess the safety of all pesticide tolerances 
existing at the time of its enactment. (21 U.S.C. 346a(q)). EPA was 
given 10 years to reassess the approximately 10,000 tolerances in 
existence in 1996. In this reassessment, EPA was required to review 
existing pesticide tolerances under the new ``reasonable certainty that 
no harm will result'' standard set forth in section 408(b)(2)(A)(i). 
(21 U.S.C. 346a(b)(2)(A)(i)). This reassessment was substantially 
completed by the August 3, 2006 deadline. Tolerance reassessment was 
generally handled in conjunction with a similar program involving 
reregistration of pesticides under FIFRA. (7 U.S.C. 136a-1). 
Reassessment and reregistration decisions were generally combined in a 
document labeled a Reregistration Eligibility Decision (``RED'').
    5. Estrogenic substances screening program. The FQPA also imposed 
requirements regarding creation of an estrogenic substances screening 
program. Section 408(p) gives EPA 2 years from enactment of the FQPA to 
``develop a screening program ... to determine whether [pesticide 
chemicals and certain other substances] may have an effect in humans 
that is similar to an effect produced by a naturally occurring 
estrogen, or such other endocrine effect as the Administrator may 
designate.'' (21 U.S.C. 346a(p)(1)). This screening program must use 
``appropriate validated test systems and scientifically relevant 
information.'' (Id.). Once the program is developed, EPA is required to 
take public comment and seek independent scientific review of it. 
Following the period for public comment and scientific review, and not 
later than 3 years following enactment of the FQPA, EPA is directed to 
``implement the program.'' (21 U.S.C. 346a(p)(2)).
    The scope of the estrogenic screening program was expanded by an 
amendment to the Safe Drinking Water Act (``SDWA'') passed 
contemporaneously with the FQPA. That amendment gave EPA the authority 
to provide for the testing, under the FQPA estrogenic screening 
program, ``of any other substance that may be found in sources of 
drinking water if the Administrator determines that a substantial 
population may be exposed to such substance.'' (42 U.S.C. 300j-17).

B. EPA Risk Assessment for Tolerances--Policy and Practice

    1. The safety determination - risk assessment. To assess risk of a 
pesticide tolerance, EPA combines information on pesticide toxicity 
with information regarding the route, magnitude, and duration of 
exposure to the pesticide. The risk assessment process involves four 
distinct steps: (1) Identification of the toxicological hazards posed 
by a pesticide; (2) determination of the ``level of concern'' with 
respect to human exposure to the pesticide; (3) estimation of human 
exposure to the pesticide; and (4) characterization of risk posed to 
humans by the pesticide based on comparison of human exposure to the 
level of concern.
    a. Hazard identification. In evaluating toxicity or hazard, EPA 
reviews toxicity studies, primarily in laboratory animals,

[[Page 42686]]

to identify any adverse effects on the test subjects. Animal studies 
typically involve investigating a broad range of endpoints including 
gross and microscopic effects on organs and tissues, functional effects 
on bodily organs and systems, effects on blood parameters (such as red 
blood cell count, hemoglobin concentration, hematocrit, and a measure 
of clotting potential), effects on the concentrations of normal blood 
chemicals (including glucose, total cholesterol, urea nitrogen, 
creatinine, total protein, total bilirubin, albumin, hormones, and 
enzymes such as alkaline phosphatase, alanine aminotransfersase and 
cholinesterases), and behavioral or other gross effects identified 
through clinical observation and measurement. EPA examines whether 
adverse effects are caused by either short-term (e.g., ``acute'') or 
longer-term (e.g., ``chronic'') pesticide exposure and the effects of 
pre-natal and post-natal exposure in animals.
    EPA also considers whether the adverse effect has a threshold - a 
level below which exposure has no appreciable chance of causing the 
adverse effect. For non-threshold effects, EPA assumes that any 
exposure to the substance increases the risk that the adverse effect 
may occur. At present, EPA only considers one adverse effect, the 
chronic effect of cancer, to potentially be a non-threshold effect. 
(Ref. 4 at 8-9). Not all carcinogens, however, pose a risk at any 
exposure level (i.e., ``a non-threshold effect or risk''). Advances in 
the understanding of the mode of action of carcinogenesis have 
increasingly led EPA to conclude that some pesticides that cause 
carcinogenic effects in animal studies only cause such effects above a 
certain threshold of exposure. EPA has traditionally considered non-
cancer adverse effects on the endocrine system to be threshold effects; 
that determination is being reexamined in conjunction with the 
endocrine disruptor screening program.
    b. Level of concern/dose-response analysis. Once a pesticide's 
potential hazards are identified, EPA determines a toxicological level 
of concern for evaluating the risk posed by human exposure to the 
pesticide. In this step of the risk assessment process, EPA essentially 
evaluates the levels of exposure to the pesticide at which effects 
might occur. An important aspect of this determination is assessing the 
relationship between exposure (dose) and response (often referred to as 
the dose-response analysis). EPA follows differing approaches to 
identifying a level of concern for threshold and non-threshold hazards.
    i. Threshold effects. In examining the dose-response relationship 
for a pesticide's threshold effects, EPA evaluates an array of toxicity 
studies on the pesticide. In each of these studies, EPA attempts to 
identify the lowest observed adverse effect level (``LOAEL'') and the 
next lower dose at which there are no observed adverse affect levels 
(``NOAEL''). Generally, EPA will use the lowest NOAEL from the 
available studies as a starting point (called ``the Point of 
Departure'') in estimating the level of concern for humans. (Ref. 4 at 
9 (The Point of Departure ``is simply the toxic dose that serves as the 
`starting point' in extrapolating a risk to the human population.'')). 
At times, however, EPA will use a LOAEL from a study as the Point of 
Departure when no NOAEL is identified in that study and the LOAEL is 
close to, or lower than, other relevant NOAELs. The Point of Departure 
is in turn used in choosing a level of concern. EPA will make separate 
determinations as to the Points of Departure, and correspondingly 
levels of concern, for both short and long exposure periods as well as 
for the different routes of exposure (oral, dermal, and inhalation).
    In estimating and describing the level of concern, the Point of 
Departure is at times used differently depending on whether the risk 
assessment addresses dietary or non-dietary exposures. For dietary 
risks, EPA uses the Point of Departure to calculate an acceptable level 
of exposure or reference dose (``RfD''). The RfD is calculated by 
dividing the Point of Departure by all applicable safety or uncertainty 
factors. Typically, EPA uses a baseline safety/uncertainty factor equal 
to 100. That value includes a factor of ten (``10X'') where EPA is 
using data from laboratory animals to reflect potentially greater 
sensitivity in humans than animals and a factor of 10X to account for 
potential variations in sensitivity among members of the human 
population as well as other unknowns. Additional safety factors may be 
added to address data deficiencies or concerns raised by the existing 
data. Under the FQPA, an additional safety factor of 10X is 
presumptively applied to protect infants and children, unless reliable 
data support selection of a different factor. This FQPA additional 
safety factor largely replaces pre-FQPA EPA practice regarding 
additional safety factors. (Ref. 5 at 4-11).
    In implementing FFDCA section 408, EPA's Office of Pesticide 
Programs, also calculates a variant of the RfD referred to as a 
Population Adjusted Dose (``PAD''). A PAD is the RfD divided by any 
portion of the FQPA safety factor that does not correspond to one of 
the traditional additional safety factors used in general Agency risk 
assessments. (Ref. 5 at 13-16). The reason for calculating PADs is so 
that other parts of the Agency, which are not governed by FFDCA section 
408, can, when evaluating the same or similar substances, easily 
identify which aspects of a pesticide risk assessment are a function of 
the particular statutory commands in FFDCA section 408. Today, RfDs and 
PADs are generally calculated for both acute and chronic dietary risks 
although traditionally a RfD or PAD was only calculated for chronic 
dietary risks. Throughout this document general references to EPA's 
calculated safe dose are denoted as a RfD/PAD.
    For non-dietary, and combined dietary and non-dietary, risk 
assessments of threshold effects, the toxicological level of concern is 
not expressed as a RfD/PAD but rather in terms of an acceptable (or 
``target'') margin of exposure (``MOE'') between human exposure and the 
Point of Departure. The ``margin'' of interest is the ratio between 
human exposure and the Point of Departure which is calculated by 
dividing human exposure into the Point of Departure. An acceptable MOE 
is generally considered to be a margin at least as high as the product 
of all applicable safety factors for a pesticide. For example, if a 
pesticide needs a 10X factor to account for inter-species differences, 
10X factor for intra-species differences, and 10X factor for the FQPA 
children's safety provision, the safe or target MOE would be a MOE of 
at least 1,000. What that means is that for the pesticide to meet the 
safety standard, human exposure to the pesticide would have to be at 
least 1,000 times smaller than the Point of Departure. Like RfD/PADs, 
specific target MOEs are selected for exposures of different durations. 
For non-dietary exposures, EPA typically examines short-term, 
intermediate-term, and long-term exposures. Additionally, target MOEs 
may be selected based on both the duration of exposure and the various 
routes of non-dietary exposure - dermal, inhalation, and oral.
    ii. Non-threshold effects. For risk assessments for non-threshold 
effects, EPA does not use the RfD/PAD or MOE approach to choose a level 
of concern if quantification of the risk is deemed appropriate. Rather, 
EPA calculates the slope of the dose-response curve for the non-
threshold effects from relevant studies using a linear, low-dose 
extrapolation model that assumes that any amount of exposure will lead 
to some degree of risk. This dose-response

[[Page 42687]]

analysis will be used in the risk characterization stage to estimate 
the risk to humans of the non-threshold effect. Linear, low-dose 
extrapolation is typically used as the default approach for estimating 
the risk to carcinogens, unless there are mode of action data 
indicating a threshold response (or nonlinearity).
    c. Estimating human exposure. Risk is a function of both hazard and 
exposure. Thus, equally important to the risk assessment process as 
determining the hazards posed by a pesticide and the toxicological 
level of concern for those hazards is estimating human exposure. Under 
FFDCA section 408, EPA is concerned not only with exposure to pesticide 
residues in food but also exposure resulting from pesticide 
contamination of drinking water supplies and from use of pesticides in 
the home or other non-occupational settings. (See 21 U.S.C. 
346a(b)(2)(D)(vi)).
    i. Exposure from food. There are two critical variables in 
estimating exposure in food: (1) The types and amount of food that is 
consumed; and (2) the residue level in that food. Consumption is 
estimated by EPA based on scientific surveys of individuals' food 
consumption in the United States conducted by the USDA. (Ref. 4 at 12). 
Information on residue values comes from a range of sources including 
crop field trials, data on pesticide reduction (or concentration) due 
to processing, cooking, and other practices, information on the extent 
of usage of the pesticide, and monitoring of the food supply. (Id. at 
17).
    In assessing exposure from pesticide residues in food, EPA, for 
efficiency's sake, follows a tiered approach in which it, in the first 
instance, assesses exposure using the worst case assumptions that 100 
percent of the crop in question is treated with the pesticide and 100 
percent of the food from that crop contains pesticide residues at the 
tolerance level. (Id. at 11). When such an assessment shows no risks of 
concern, a more complex risk assessment is unnecessary. By avoiding a 
more complex risk assessment, EPA's resources are conserved and 
regulated parties are spared the cost of any additional studies that 
may be needed. If, however, a first tier assessment suggests there 
could be a risk of concern, EPA then attempts to refine its exposure 
assumptions to yield a more realistic picture of residue values through 
use of data on the percent of the crop actually treated with the 
pesticide and data on the level of residues that may be present on the 
treated crop. These latter data are used to estimate what has been 
traditionally referred to by EPA as ``anticipated residues.''
    Use of percent crop treated data and anticipated residue 
information is appropriate because EPA's worst-case assumptions of 100 
percent treatment and residues at tolerance value significantly 
overstate residue values. There are several reasons this is true. 
First, all growers of a particular crop would rarely choose to apply 
the same pesticide to that crop; generally, the proportion of the crop 
treated with a particular pesticide is significantly below 100 percent. 
(70 FR 46706, 46731 (August 10, 2005)). Second, the tolerance value 
represents a high end or worst case value. Tolerance values are chosen 
only after EPA has evaluated data from experimental crop field trials 
in which the pesticide has been used in a manner, consistent with the 
draft FIFRA label, that is likely to produce the highest residue in the 
crop in question (e.g., maximum application rate, maximum number of 
applications, minimum pre-harvest interval between last pesticide 
application and harvest). (Refs. 4 and 6). These crop field trials are 
generally conducted in several fields at several geographical 
locations. (Id. at 5, 7 and Tables 1 and 5). Several samples are then 
gathered from each field and analyzed. (Id. at 53). Generally, the 
results from such field trials show that the residue levels for a given 
pesticide use will vary from as low as non-detectable to measurable 
values in the parts per million (``ppm'') range with the majority of 
the values falling at the lower part of the range. (70 FR at 46731). 
EPA uses a statistical procedure to analyze the field trial results and 
identify the upper bound of expected residue values. This upper bound 
value is used as the tolerance value. (Ref. 7). There may be some 
commodities from a treated crop that approach the tolerance value where 
the maximum label rates are followed, but most generally fall 
significantly below the tolerance value. If less than the maximum legal 
rate is applied, residues will be even lower. Third, residue values in 
the field do not take into account the lowering of residue values that 
frequently occurs as a result of degradation over time and through food 
processing and cooking.
    EPA uses several techniques to refine residue value estimates. 
(Ref. 4 at 17-28). First, where appropriate, EPA will take into account 
all the residue values reported in the crop field trials, either 
through use of an average or individually. Second, EPA will consider 
data showing what portion of the crop is not treated with the 
pesticide. Third, data can be produced showing pesticide degradation 
and decline over time, and the effect of commercial and consumer food 
handling and processing practices. Finally, EPA can consult monitoring 
data gathered by the FDA, the USDA, or pesticide registrants, on 
pesticide levels in food at points in the food distribution chain 
distant from the farm, including retail food establishments.
    Another critical component of the exposure assessment is how data 
on consumption patterns are combined with data on pesticide residue 
levels in food. Traditionally, EPA has calculated exposure by simply 
multiplying average consumption by average residue values for 
estimating chronic risks and high-end consumption by maximum residue 
values for estimating acute risks. Using average residues is a 
realistic approach for chronic risk assessment due to the fact that 
variations in residue levels and consumption amounts average out over 
time. Using average values is inappropriate for acute risk assessments, 
however, because in assessing acute exposure situations it matters how 
much of each treated food a given consumer eats and what the residue 
levels are in the particular foods consumed. Yet, using maximum residue 
values for acute risk assessment tends to greatly overstate exposure 
because it is unlikely that a person would consume at a single meal 
multiple food components bearing high-end residues. To take into 
account the variations in short-term consumption patterns and food 
residue values for acute risk assessments, EPA has more recently begun 
using probabilistic modeling techniques for estimating exposure when 
more simplistic models appear to show risks of concerns.
    All of these refinements to the exposure assessment process, from 
use of food monitoring data through probabilistic modeling, can have 
dramatic effects on the level of exposure predicted, reducing worst 
case estimates by 1 or 2 orders of magnitude or more. (Ref. 8 at 16-17; 
70 FR 46706, 46732 (August 10, 2005).
    ii. Exposure from water. EPA may use either or both field 
monitoring data and mathematical water exposure models to generate 
pesticide exposure estimates in drinking water. Monitoring and modeling 
are both important tools for estimating pesticide concentrations in 
water and can provide different types of information. Monitoring data 
can provide estimates of pesticide concentrations in water that are 
representative of specific agricultural or residential pesticide 
practices and under environmental conditions associated with a sampling 
design. Although monitoring data can provide a

[[Page 42688]]

direct measure of the concentration of a pesticide in water, it does 
not always provide a reliable estimate of exposure because sampling may 
not occur in areas with the highest pesticide use, and/or the sampling 
may not occur when the pesticides are being used.
    In estimating pesticide exposure levels in drinking water, EPA most 
frequently uses mathematical water exposure models. EPA's models are 
based on extensive monitoring data and detailed information on soil 
properties, crop characteristics, and weather patterns. (69 FR 30042, 
30058-30065 (May 26, 2004)). These models calculate estimated 
environmental concentrations of pesticides using laboratory data that 
describe how fast the pesticide breaks down to other chemicals and how 
it moves in the environment. These concentrations can be estimated 
continuously over long periods of time, and for places that are of most 
interest for any particular pesticide. Modeling is a useful tool for 
characterizing vulnerable sites, and can be used to estimate peak 
concentrations from infrequent, large storms.
    iii. Residential exposures. Generally, in assessing residential 
exposure to pesticides EPA relies on its Residential Standard Operating 
Procedures (``SOPs''). (Ref. 9). The SOPs establish models for 
estimating application and post-application exposures in a residential 
setting where pesticide-specific monitoring data are not available. 
SOPs have been developed for many common exposure scenarios including 
pesticide treatment of lawns, garden plants, trees, swimming pools, 
pets, and indoor surfaces including crack and crevice treatments. The 
SOPs are based on existing monitoring and survey data including 
information on activity patterns, particularly for children. Where 
available, EPA relies on pesticide-specific data in estimating 
residential exposures.
    d. Risk characterization. The final step in the risk assessment is 
risk characterization. In this step, EPA combines information from the 
first three steps (hazard identification, level of concern/dose-
response analysis, and human exposure assessment) to quantitatively 
estimate the risks posed by a pesticide. Separate characterizations of 
risk are conducted for different durations of exposure. Additionally, 
separate and, where appropriate, aggregate characterizations or risk 
are conducted for the different routes of exposure (dietary and non-
dietary).
    For threshold risks, EPA estimates risk in one of two ways. Where 
EPA has calculated a RfD/PAD, risk is estimated by expressing human 
exposure as a percentage of the RfD/PAD. Exposures lower than 100 
percent of the RfD/PAD are generally not of concern. Alternatively, EPA 
may express risk by comparing the MOE between estimated human exposure 
and the Point of Departure with the acceptable or target MOE. As 
described above, the acceptable or target MOE is the product of all 
applicable safety factors. To calculate the actual MOE for a pesticide, 
estimated human exposure to the pesticide is divided into the Point of 
Departure. In contrast to the RfD/PAD approach, the higher the MOE, the 
safer the pesticide. Accordingly, if the target MOE for a pesticide is 
100, MOEs equal to or exceeding 100 would generally not be of concern.
    As a conceptual matter, the RfD/PAD and MOE approaches are 
fundamentally equivalent. For a given risk and given exposure of a 
pesticide, if exposure to a pesticide were found to be acceptable under 
an RfD/PAD analysis it would also pass under the MOE approach, and 
vice-versa. However, for any specific pesticide, risk assessments for 
different exposure durations or routes may yield different results. 
This is a function not of the choice of the RfD/PAD or MOE approach but 
of the fact that the levels of concern and the levels of exposure may 
differ depending on the duration and route of exposure.
    For non-threshold risks (generally, cancer risks), EPA uses the 
slope of the dose-response curve for a pesticide in conjunction with an 
estimation of human exposure to that pesticide to estimate the 
probability of occurrence of additional adverse effects. For non-
threshold cancer risks, EPA generally considers cancer risk to be 
negligible if the probability of increased cancer cases falls within 
the range of 1 in 1 million. Risks exceeding values within that range 
would raise a risk concern.
    2. EPA policy on the children's safety factor. As the above brief 
summary of EPA's risk assessment practice indicates, the use of safety 
factors plays a critical role in the process. This is true for 
traditional 10X safety factors to account for potential differences 
between animals and humans when relying on studies in animals (inter-
species safety factor) and potential differences among humans (intra-
species safety factor) as well as the FQPA's additional 10X children's 
safety factor.
    In applying the children's safety factor provision, EPA has 
interpreted it as imposing a presumption in favor of applying an 
additional 10X safety factor. (Ref. 5 at 4, 11). Thus, EPA generally 
refers to the additional 10X factor as a presumptive or default 10X 
factor. EPA has also made clear, however, that this presumption or 
default in favor of the additional 10X is only a presumption. The 
presumption can be overcome if reliable data demonstrate that a 
different factor is safe for children. (Id.). In determining whether a 
different factor is safe for children, EPA focuses on the three factors 
listed in section 408(b)(2)(C) - the completeness of the toxicity 
database, the completeness of the exposure database, and potential pre- 
and post-natal toxicity. In examining these factors, EPA strives to 
make sure that its choice of a safety factor, based on a weight-of-the-
evidence evaluation, does not understate the risk to children. (Id. at 
24-25, 35).
    3. EPA policy on cholinesterase inhibition as a regulatory 
endpoint. Cholinesterase inhibition is a disruption of the normal 
process in the body by which the nervous system chemically communicates 
with muscles and glands. Communication between nerve cells and a target 
cell (i.e., another nerve cell, a muscle fiber, or a gland) is 
facilitated by the chemical, acetylcholine. When a nerve cell is 
stimulated it releases acetylcholine into the synapse (or space) 
between the nerve cell and the target cell. The released acetylcholine 
binds to receptors in the target cell, stimulating the target cell in 
turn. As EPA has explained, ``the end result of the stimulation of 
cholinergic pathway(s) includes, for example, the contraction of smooth 
(e.g., in the gastrointestinal tract) or skeletal muscle, changes in 
heart rate or glandular secretion (e.g., sweat glands) or communication 
between nerve cells in the brain or in the autonomic ganglia of the 
peripheral nervous system.'' (Ref. 10 at 10).
    Acetylcholinesterase is an enzyme that breaks down acetylcholine 
and terminates its stimulating action in the synapse between nerve 
cells and target cells. When acetylcholinesterase is inhibited, 
acetylcholine builds up prolonging the stimulation of the target cell. 
This excessive stimulation potentially results in a broad range of 
adverse effects on many bodily functions including muscle cramping or 
paralysis, excessive glandular secretions, or effects on learning, 
memory, or other behavioral parameters. Depending on the degree of 
inhibition these effects can be serious, even fatal.
    EPA's cholinesterase inhibition policy statement explains EPA's 
approach to evaluating the risks posed by cholinesterase-inhibiting 
pesticides such as DDVP. (Ref. 10). The policy focuses on three types 
of effects associated with cholinesterase-

[[Page 42689]]

inhibiting pesticides that may be assessed in animal and human 
toxicological studies: (1) Physiological and behavioral/functional 
effects; (2) cholinesterase inhibition in the central and peripheral 
nervous system; and (3) cholinesterase inhibition in red blood cells 
and blood plasma. The policy discusses how such data should be 
integrated in deriving an acceptable dose (RfD/PAD) for a 
cholinesterase-inhibiting pesticide.
    Clinical signs or symptoms of cholinesterase inhibition in humans, 
the policy concludes, provide the most direct evidence of the adverse 
consequences of exposure to cholinesterase-inhibiting pesticides. 
Nonetheless, as the policy notes, due to strict ethical limitations, 
studies in humans are ``quite limited.'' (Id. at 19). Although animal 
studies can also provide direct evidence of cholinesterase inhibition 
effects, animal studies cannot easily measure cognitive effects of 
cholinesterase inhibition such as effects on perception, learning, and 
memory. For these reasons, the policy recommends that ``functional data 
obtained from human and animal studies should not be relied on solely, 
to the exclusion of other kinds of pertinent information, when weighing 
the evidence for selection of the critical effect(s) that will be used 
as the basis of the RfD or RfC.'' (Id. at 20).
    After clinical signs or symptoms, cholinesterase inhibition in the 
nervous system provides the next most important endpoint for evaluating 
cholinesterase-inhibiting pesticides. Although cholinesterase 
inhibition in the nervous system is not itself regarded as a direct 
adverse effect, it is ``generally accepted as a key component of the 
mechanism of toxicity leading to adverse cholinergic effects.'' (Id. at 
25). As such, the policy states that it should be treated as ``direct 
evidence of potential adverse effects'' and ``data showing this 
response provide valuable information in assessing potential hazards 
posed by anticholinesterase pesticides.'' (Id.). Unfortunately, useful 
data measuring cholinesterase inhibition in the central and peripheral 
nervous systems has only been relatively rarely captured by standard 
toxicology testing, particularly as to peripheral nervous system 
effects. For central nervous system effects, however, more recent 
neurotoxicity studies ``have sought to characterize the time course of 
inhibition in ... [the] brain, including brain regions, after acute and 
90-day exposures.'' (Id. at 27).
    Cholinesterase inhibition in the blood is one step further removed 
from the direct harmful consequences of cholinesterase-inhibiting 
pesticides. According to the policy, inhibition of blood 
cholinesterases ``is not an adverse effect, but may indicate a 
potential for adverse effects on the nervous system.'' (Id. at 28). The 
policy states that ``[a]s a matter of science policy, blood 
cholinesterase data are considered appropriate surrogate measures of 
potential effects on peripheral nervous system acetylcholinesterase 
activity in animals, for central nervous system (``CNS'') 
acetylcholinesterase activity in animals when CNS data are lacking and 
for both peripheral and central nervous system acetylcholinesterase in 
humans.'' (Id. at 29). The policy notes that ``there is often a direct 
relationship between a greater magnitude of exposure [to a 
cholinesterase-inhibiting pesticide] and an increase in incidence and 
severity of clinical signs and symptoms as well as blood cholinesterase 
inhibition.'' (Id. at 30). Thus, the policy regards blood 
cholinesterase data as ``appropriate endpoints for derivation of 
reference doses or concentrations when considered in a weight-of-the-
evidence analysis of the entire database ....'' (Id. at 29). Between 
cholinesterase inhibition measured in red blood cell (``RBC'') or blood 
plasma, the policy states a preference for reliance on RBC 
acetylcholinesterase measurements because plasma is composed of a 
mixture of acetylcholinesterase and butyrylcholinesterase, and 
inhibition of the latter is less clearly tied to inhibition of 
acetylcholinesterase in the nervous system. (Id. at 29, 32).
    If a measure of cholinesterase inhibition (e.g., RBC 
cholinesterase) is being considered as a potential adverse effect or 
surrogate for an adverse effect, the policy advises that the level of 
inhibition must be critically evaluated ``in the context of both 
statistical and biological significance.'' (Id. at 37) (emphasis in 
Original). The policy notes that ``[n]o fixed percentage of change 
(e.g., 20% for cholinesterase enzyme inhibition) is predetermined to 
separate adverse from non-adverse effects.'' (Id.). Rather, the policy 
explains that ``OPP's experience with the review of toxicity studies 
with cholinesterase-inhibiting substances shows that differences 
between pre- and post-exposure of 20% or more in enzyme levels is 
nearly always statistically significant and would generally be viewed 
as biologically significant.'' (Id. at 37-38). The policy recommends 
that ``[t]he biological significance of statistically-significant 
changes of less than 20% would have to be judged on a case-by-case 
basis, noting, in particular the pattern of changes in the enzyme 
levels and the presence or absence of accompanying clinical signs and/
or symptoms.'' (Id. at 38). The policy notes that similar or higher 
levels of cholinesterase inhibition are used ``in monitoring workers 
for occupational exposures (even in the absence of signs, symptoms, or 
other behavioral effects).'' (Id. at 31). For example, the policy 
points out that the California Department of Health Services requires 
that workers exposed to toxic chemicals such as organophosphate 
pesticides be removed from the workplace if ``red blood cell 
cholinesterase levels show 30% or greater inhibition,'' and that the 
World Health Organization ``has guidelines with the same RBC action 
levels (i.e., 30% or greater inhibition).'' (Id.).

C. Endocrine Disruptor Screening Program

    The 1996 FQPA and SWDA amendments directed EPA to develop and 
implement an endocrine screening program. To aid in the design of this 
program called for in the FQPA and SDWA amendments, EPA created the 
Endocrine Disruptor Screening and Testing Advisory Committee 
(``EDSTAC''), which was comprised of members representing the 
commercial chemical and pesticides industries, federal and state 
agencies, worker protection and labor organizations, environmental and 
public health groups, and research scientists. (63 FR 71542, 71544, 
Dec. 28, 1998). The EDSTAC presented a comprehensive report in August 
1998 addressing both the scope and elements of the endocrine screening 
program. (Ref. 11). The EDSTAC's recommendations were largely adopted 
by EPA.
    As recommended by EDSTAC, EPA expanded the scope of the program 
from focusing only on estrogenic effects to include other effects on 
the endocrine system (i.e., androgenic and thyroid effects). (63 FR at 
71545). Further, EPA, again on the EDSTAC's recommendation, chose to 
include both human and ecological effects in the program. (Id.). 
Finally, based on EDSTAC's recommendation, EPA established the universe 
of chemicals to be screened to include not just pesticides but also a 
wide range of other chemical substances. (Id.). As to the program 
elements, EPA adopted EDSTAC's recommended two-tier approach with the 
first tier involving screening ``to identify substances that have the 
potential to interact with the endocrine system'' and the second tier 
involving testing ``to determine whether the substance causes adverse 
effects,

[[Page 42690]]

identify the adverse effects caused by the substance, and establish a 
quantitative relationship between the dose and the adverse effect.'' 
(Id.). Tier 1 screening is limited to evaluating whether a substance is 
``capable of interacting with'' the endocrine system, and is ``not 
sufficient to determine whether a chemical substance may have an effect 
in humans that is similar to an effect produced by naturally occurring 
hormones.'' (Id. at 71550). Based on the results of Tier 1 screening, 
EPA will decide whether Tier 2 testing is needed. Importantly, ``[t]he 
outcome of Tier 2 is designed to be conclusive in relation to the 
outcome of Tier 1 and any other prior information. Thus, a negative 
outcome in Tier 2 will supersede a positive outcome in Tier 1.'' (Id. 
at 71554-71555).
    The EDSTAC provided detailed recommendations for Tier 1 screening 
and Tier 2 testing. The panel of the EDSTAC that devised these 
recommendations was comprised of distinguished scientists from 
academia, government, industry, and the environmental community. (Ref. 
11 at Appendix B). As suggested by the EDSTAC, EPA has proposed a 
battery of short-term in vitro and in vivo assays for the Tier 1 
screening exercise. (63 FR at 71550-71551). Validation of all but one 
of these assays is complete. As to Tier 2 testing, EPA, on the 
recommendation of the EDSTAC, has proposed using five longer-term 
reproduction studies that, with one exception, ``are routinely 
performed for pesticides with widespread outdoor exposures that are 
expected to affect reproduction.'' (Id. at 71555). EPA is examining, 
pursuant to the suggestion of the EDSTAC, modifications to these 
studies to enhance their ability to detect endocrine effects.
    EPA has published a draft list of the first group of chemicals that 
will be tested under the Agency's endocrine disruptor screening 
program. (72 FR 33486 (June 18, 2007)). The draft list was produced 
based solely on the exposure potential of the chemicals and EPA has 
emphasized that ``[n]othing in the approach for generating the initial 
list provides a basis to infer that by simply being on this list these 
chemicals are suspected to interfere with the endocrine systems of 
humans or other species, and it would be inappropriate to do so.'' 
(Id.)

D. EPA's Human Research Rule

    EPA decisions regarding the ethics of human studies are governed by 
the Protection for Subjects in Human Research final rule (``Human 
Research rule''), which significantly strengthened and expanded 
protections for subjects of human research. (71 FR 6138 (February 6, 
2006)). The framework of the Human Research rule rests on the basic 
principle that EPA will not, in its actions, rely on data derived from 
unethical research. The rule divides studies involving intentional 
dosing of human subjects into two groups: ``new'' studies - those 
initiated after April 7, 2006 (the effective date of the rule) - and 
``old'' studies - those initiated before April 7, 2006. The Human 
Research Rule forbids EPA from relying on data from any ``new'' study, 
unless EPA has adequate information to determine that the research was 
conducted in substantial compliance with the ethical requirements 
contained therein. (40 CFR. 26.1705). These ethical rules are derived 
primarily from the ``Common Rule,'' (40 CFR part 26), a rule setting 
ethical parameters for studies conducted or supported by the federal 
government. In addition to requiring informed consent and protection of 
the safety of the subjects, among other things, the rule specifies that 
``[r]isks to subjects [must be] reasonable in relation to . . . the 
importance of the knowledge that may reasonably be expected to result 
[from the study].'' (40 CFR 26.1111(a)(2)). In other words, a study 
would be judged unethical if it did not have scientific value 
outweighing any risks to the test subjects.
    As to ``old'' studies, the Human Research Rule forbids EPA from 
relying on such data if there is clear and convincing evidence that the 
conduct of the research was fundamentally unethical or significantly 
deficient with respect to the ethical standards prevailing at the time 
the research was conducted. (40 CFR 26.1704). EPA has indicated that in 
evaluating ``the ethical standards prevailing at the time the research 
was conducted'' it will consider the Nuremburg Code, various editions 
of the Declaration of Helsinki, the Belmont Report, and the Common 
Rule, as among the standards that may be applicable to any particular 
study. (71 FR at 6161). Further, reflecting the concern that 
scientifically invalid data are ``always unethical,'' (71 FR at 6160), 
the rule limits the human research that can be relied upon by EPA to 
``scientifically valid and relevant data.'' (40 CFR 26.1701).
    Whether the data are ``new'' or ``old,'' the Human Research rule 
forbids EPA from relying on data from any study involving intentional 
exposure of pregnant women, fetuses, or children subject to a very 
limited exception. (40 CFR 26.1703, 1706).
    To aid EPA in making scientific and ethical determinations under 
the Human Research rule, the rule established an independent Human 
Studies Review Board (``HSRB'') to review both proposals for new 
research (``new'' studies) and reports of completed human research 
(``old'' studies) on which EPA proposes to rely. (40 CFR 26.1603). The 
rule directs that HSRB shall be comprised of non-EPA employees ``who 
have expertise in fields appropriate for the scientific and ethical 
review of human research, including research ethics, biostatistics, and 
human toxicology.'' (40 CFR 26.1603(a)). If EPA decides to rely on the 
results from ``old'' research conducted to identify or measure a toxic 
effect, EPA must submit the results of its assessment to the HSRB for 
evaluation of the ethical and scientific merit of the research. (40 CFR 
26.1602(b)(2)).
    EPA has established the HSRB as a federal advisory committee under 
the Federal Advisory Committee Act (``FACA'') to take advantage of 
``the benefits of the transparency and opportunities for public 
participation'' that accompany a FACA committee. (71 FR at 6156). The 
HSRB, as appointed by EPA, contains approximately 16 distinguished 
experts in the fields of bioethics, biostatistics, human health risk 
assessment and human toxicology, primarily from academia. (Ref. 12).
    NRDC and other parties have challenged the legality of the Human 
Research rule. (NRDC v. U.S. EPA, No. 06-0820-ag (2d Cir.)). A decision 
on this challenge is presently pending before the United States Court 
of Appeals for the Second Circuit.

IV. Regulatory History of DDVP

A. In General

    1. DDVP use. Dichlorvos (2, 2-dichlorovinyl dimethyl phosphate), 
also known as DDVP, is an insecticide used in controlling flies, 
mosquitoes, gnats, cockroaches, fleas, and other insect pests. (Ref. 
3). DDVP is registered for use on agricultural sites; commercial, 
institutional, and industrial sites; and for domestic use in and around 
homes. Agricultural and other commercial uses include in greenhouses; 
mushroom houses; storage areas for bulk, packaged and bagged raw and 
processed agricultural commodities; food manufacturing/processing 
plants; animal premises; and non-food areas of food-handling 
establishments. It is also registered for treatment of cattle, poultry 
and swine. DDVP is not registered for direct use on any field grown 
commodities. Currently, there are 27 tolerances listed in 40 CFR 
180.235 for DDVP on agricultural (food and feed) crops and animal 
commodities. DDVP is

[[Page 42691]]

applied with aerosols, fogging equipment, and spray equipment, and 
through use of impregnated materials such as resin strips which result 
in slow release of the pesticide. The current registrant for the 
technical active ingredient, DDVP, is Amvac Chemical Corporation 
(``Amvac'').
    2. DDVP risks. The following information on the assessment of the 
risks posed by DDVP is drawn from EPA's decision on the reassessment of 
DDVP tolerances and its response to NRDC's petition.
    DDVP is a chlorinated organophosphate pesticide which inhibits 
plasma, RBC, and brain cholinesterase in a variety of species. (Ref. 3 
at 122-123). Subchronic and chronic oral DDVP exposures to rats and 
dogs as well as chronic inhalation DDVP exposure to rats resulted in 
significant decreases in plasma, RBC and/or brain cholinesterase 
activity. However, DDVP does not cause delayed neurotoxicity in the 
hen. Repeated, oral subchronic DDVP exposures in male humans were 
associated with statistically and biologically significant decreases in 
RBC cholinesterase inhibition. There was no evidence of increased 
susceptibility to young animals following in utero DDVP exposure to rat 
and rabbit fetuses as well as pre/post natal DDVP exposure to rats in 
developmental, reproduction, and comparative cholinesterase studies. 
Evidence of sensitivity in the young was seen in one parameter, 
auditory startle amplitude, in a developmental neurotoxicity study; 
however, the effects in the rat pups here was at levels well above 
levels which result in RBC cholinesterase inhibition. Cancer studies 
with DDVP provide suggestive evidence of DDVP's potential human 
carcinogenicity; however, following the advice of numerous independent 
scientific panels, EPA has determined that DDVP poses a negligible 
cancer risk to humans due to the lack of relevance to humans of the 
tumors identified in the DDVP cancer studies. (72 FR at 68671-68673).
    Inhibition of cholinesterase activity was the toxicity endpoint 
selected to assess hazards for all acute and chronic dietary exposures, 
as well as short-, intermediate-, and long-term (chronic) dermal, 
inhalation, and incidental oral residential exposures. Doses selected 
for the Point of Departure in determining the level of concern - i.e., 
RfD/PADs and acceptable MOEs - were based on both human and animal 
studies. (Ref. 3 at 130-135). Animal studies were used in choosing 
levels of concern for evaluating risk from acute and chronic dietary 
exposure; acute dermal exposure; and acute and chronic inhalation 
exposure. A human study was used evaluating risk from short-term 
incidental oral exposure; short-, intermediate-, and long-term dermal 
exposure; and short- and intermediate-term inhalation exposure.
    Safety factor determinations used in selecting the level of concern 
differed based on whether EPA relied on one of several different animal 
studies or a human study. For levels of concerns derived from a Point 
of Departure from an animal study, EPA generally applied a 100X safety 
factor (10X for inter-species variability and 10X for intra-human 
variability). EPA removed the 10X children's safety factor for risk 
assessments based on an animal study. For levels of concerns derived 
from a Point of Departure from the human study, EPA applied a 10X 
safety factor for intra-human variability and a 3X children's safety 
factor. (Id.).
    EPA based its decision to remove the children's safety factor when 
relying on animal data on its conclusions that (1) the toxicity 
database was complete; (2) most of the data indicated no sensitivity in 
the young and the only evidence of sensitivity occurred at levels well 
above the Points of Departure used for establishing the levels of 
concern; and (3) its estimate of human exposure to DDVP was not 
understated. EPA retained a portion of the children's safety factor 
when relying on the human study because that study did not determine a 
NOAEL. EPA concluded, however, that reliable data supported reduction 
of the 10X factor because