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TOXICOLOGICAL SCIENCES
How to Determine if an Additional 103 Safety Factor Is Needed for
Chemicals: A Case Study with Chlorpyrifos
James E. Gibson, 1 William L. Chen, and Robert K. D. Peterson
Dow AgroSciences, LLC, 9330 Zionsville Road, Indianapolis, Indiana 46268
Received September 25, 1998; accepted November 25, 1998
THE FOOD QUALITY PROTECTION ACT (FQPA) AND
ITS ASSOCIATED 103 SAFETY FACTOR
In August of 1996, the U.S. Congress passed new pesticide
food safety legislation, the Food Quality Protection Act
(FQPA). The FQPA states that “in the case of threshold effects
for purposes of clause (ii) (I) (reasonable certainty that no harm
will result), 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.
Notwithstanding such requirements for an additional margin of
safety, the Administration 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”
(EPA, 1996).
The legislative requirements of FQPA are based on the
recommendations in the National Academy of Sciences (NAS)
report (NRC, 1993), “Pesticides in the Diets of Infants and
Children,” which concluded that infants and children may have
significantly different exposures and/or responses to pesticides
than adults. Therefore, it was believed that an additional uncertainty factor may, in some cases, be needed to account for
the incomplete data.
HOW TO DETERMINE THE NEED FOR THE FQPA 103
SAFETY FACTOR
How should the risk of chemicals to infants and children be
assessed? In reviewing the EPA’s procedure for applying the
additional uncertainty factor (FQPA factor) to protect infants
and children, the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) Science Advisory Panel (SAP), in the meeting of March, 1998 (SAP, 1998), recommended a 5-step procedure: (1) hazard identification; (2) dose-response assessment;
(3) exposure assessment; (4) risk characterization; and (5)
1
To whom correspondence should be addressed at Dow AgroSciences,
LLC, 9330 Zionsville Rd., Indianapolis, IN 46268. Fax: (317) 337–3810.
E-mail: [email protected].
decision whether to apply the FQPA factor as the final step in
the process. The first four steps in this process mirror the
risk-assessment procedure outlined by the National Academy
of Sciences in 1983 (NRC, 1983), and, we believe, is the most
effective way to reach a decision in step 5. In cases where data
gaps exist, the EPA should use its “data call-in” process to try
to provide the needed information (EPA, 1997).
Hazard is the inherent ability to do harm to living organisms.
Under the current hazard-identification methodology, animal
toxicological studies are required to include the highest dose
that is sufficient to elicit a significant toxic effect; this becomes
known as the maximum tolerated dose (MTD). The MTD is
usually unrealistically high and never encountered in real life.
Therefore, it is important to conduct an exposure assessment
that will consider the route, extent, frequency, and duration of
human exposure. Furthermore, it is essential that available
pharmacokinetic, metabolic, and mechanistic data are utilized
to assess the relevance to humans of effects observed in animal
toxicity studies. This integrated toxicity and exposure assessment should be based on sound science, taking into account the
weight of the scientific evidence from all relevant data sources.
A CASE STUDY WITH CHLORPYRIFOS
Using the SAP procedure, Dow AgroSciences scientists and
independent experts have critically reviewed the toxicology
and exposure database on chlorpyrifos, with respect to the
adequacy of the existing safety factor in protecting infants and
children. The 5-step process should end with an appropriate
decision having been made regarding the need for an FQPA
103 safety factor.
Hazard Identification and Dose Response Assessment
Neurotoxicity: Organophosphate-Induced Delayed
Neuropathy (OPIDN) and Neurophysiological Effects
Epidemiology. An epidemiology panel composed of international health experts 2 concluded, after examining the rele2
James W. Albers, Department of Neurology, University of Michigan;
Philip Cole, University of Alabama at Birmingham; Ray Greenberg, Chairman,
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GIBSON, CHEN, AND PETERSON
vant data, that chlorpyrifos had not been shown to be a concern
for public health (Albers et al., 1999). The panel examined
available scientific evidence on a variety of neurological, behavioral, and immunological disorders, multiple complaints
(often called multiple chemical sensitivities), and birth defects.
After extensive review, the panel was not persuaded that exposure to chlorpyrifos-containing products caused any of these
conditions in humans. The panel’s report was submitted to the
EPA on October 20, 1997.
Reference dose (RfD). In April, 1997, a panel of independent experts 3 was convened to review and evaluate all relevant
animal and human studies, with respect to the determination of
RfDs for chlorpyrifos (Clegg and Van Gemert, 1999a,b). The
panel’s report was submitted to the EPA on December 11,
1997.
The RfD panel reviewed a toxicity database comprising the
following: biochemical data; acute-toxicity data in a number of
species; short-term studies in rats, dogs and monkeys; longterm studies in mice and rats; 3-rat-multigeneration reproduction studies; developmental studies in mice and rats; studies on
neuropathy target esterase inhibition; cognitive studies; chlorpyrifos-induced delayed neuropathy studies on hens, rats, cats
and humans; and toxicity studies using human volunteers. In
addition, several case reports were reviewed on organophosphate-induced delayed neuropathy (OPIDN) and the sensory
neuropathy potential of chlorpyrifos.
No evidence of OPIDN was found when chlorpyrifos was
tested in hens in an acute study at twice the LD50 (100 mg/kg
body weight [bw]), or in a subchronic hen study at 10 mg/kg
bw/day. The RfD Panel concluded that OPIDN was only
observed after lethal doses.
Neurotoxicity studies. Chlorpyrifos has been evaluated for
neurotoxic effects in rats, using single-dose, as well as 13-week
repeated dose, EPA FIFRA test guidelines and good laboratory
practice (GLP) conditions. The studies were published in the
scientific literature (Mattsson et al., 1996) and included a
functional observational battery, automated motor-activity testing, and comprehensive neurohistopathology testing of perfused tissues. Administration of up to 100 mg/kg bw by gavage
in the single-dose study, and up to 15 mg/kg bw/day in diet for
13 weeks in the repeated-dose study were evaluated. These
dosages provided an opportunity to characterize chlorpyrifos
over-exposure in rats the effects of which included cholinergic
Medical University of South Carolina; Jack S. Mandell, University of Minnesota; Richard R. Monson, Harvard School of Public Health; John H. Ross,
California Department of Pesticide Regulation; Wayne R. Snodgrass, Texas
Poison Center; and Anne Spurgeon, University of Birmingham, U.K.
3
James W. Albers, Department of Neurology, University of Michigan;
David J. Clegg, former Head of Pesticide Toxicology, Health Canada; Philip
S. Guzelian, Department of Medicine, University of Colorado; Marcello Lotti,
Istituto di Medicina del Lavoro, Universita di Padova; Rudy J. Richardson,
Toxicology Program, University of Michigan; and Mike Watson, former Head
of Toxicology, Pesticide Safety Directorate, U.K.
overstimulation. Single gavage doses of chlorpyrifos caused a
range of clinical signs characteristic of cholinergic overstimulation, but effects were minimal in the 13-week study and there
was no evidence of accumulation of toxicity during treatment.
Motor activity was decreased in the high dose rats at week
four, but was not significantly different from controls in subsequent weeks. The NOEL for the single-dose study was 10
mg/kg bw (LOEL was 50 mg/kg bw with minimal cholinergic
effects) and the NOEL for the 13-week study was 1 mg/kg
bw/day (LOEL was 5 mg/kg bw/day with minimal cholinergic
effects). Comprehensive neuropathological examination revealed no treatment-related lesions in either study.
Susceptibility of Infants and Children
All mammalian chlorpyrifos-toxicology studies required to
support EPA registration, including developmental and reproductive studies conducted according to FIFRA guidelines and
under GLP have been submitted and judged by the agency to
be acceptable. Chlorpyrifos did not affect fetal development or
reproduction at maternally non-toxic dosages, as noted in the
Hazard Identification Assessment Review Committee (HIARC)
report (EPA, 1998).
Relevant developmental toxicity studies in the scientific
literature, where dams were dosed, demonstrate that the fetus
and neonate are less sensitive to chlorpyrifos than the adult.
(Barone et al., 1997; Chandra et al., 1995; Chandra and Pope,
1996; Phillips et al., 1997; Tang et al., 1997).
Other published studies (Campbell et al., 1997; Moser and
Padilla, 1998; Pope and Charkraborti, 1992; Pope et al., 1991;
Song et al., 1997; Whitney et al., 1995) in which chlorpyrifos
was administered as a single dose directly to neonates are not
appropriate to assess the relative sensitivity of young animals
compared to adults, because:
(1) The routes of exposure used in animals were often
inappropriate as potential routes of exposure in human infants
and children. Most of the animal data were generated with
subcutaneous or interperitoneal injections, which are not encountered with human subjects.
(2) Very high MTD of chlorpyrifos (defined as the dose
producing no more than 10% mortality; 18 to 45 mg/kg bw)
were administered to juveniles, and these doses were much
larger than a neonate or infant could absorb via an appropriate
route of exposure.
(3) Other data indicate that, at lower levels of exposure,
differences in sensitivity are minimal or non-existent. For
example, Pope and Liu (1997) have shown that juveniles are
not more sensitive than adults to neurochemical alterations
following repeated lower-level exposures.
The FIFRA Science Advisory Panel (SAP) report of March,
1998, in discussing the FQPA 103 safety factor, also raised
concerns over these acute high dose studies (SAP, 1998):
DETERMINING THE 103 SAFETY FACTOR
Some data are presently available . . . much of this existing information
was generated in acute treatment experiments, frequently at very high
exposure levels. Such data may not be appropriate to extrapolate to
low-dose situations (e.g., organophosphates), where much, if not all, of
the age-related differences may be attributable to differences in the
magnitude of activity of detoxification enzymes. In such cases, differences in toxicity between adults and juveniles would be substantially
greater at high doses where detoxification mechanisms are saturated than
at low doses where they are not.
Developmental neurotoxicity study. In May 1998, Dow
AgroSciences submitted a developmental neurotoxicity study
to the EPA, which was conducted according to FIFRA guidelines and under GLP (Hoberman, 1998; Maurissen, 1998). The
study was designed in concert with EPA to ensure that it
addressed the EPA’s concerns.
A series of experiments were performed where pregnant
female rats (dams) were given chlorpyrifos by gavage daily,
starting from gestation day 6 through lactation day 10 at
dosages of 0, 0.3, 1, and 5 mg/kg bw. This represented a
repeated low dose exposure lasting 25 days, wherein the fetuses were exposed to the compound through the mother, and
postnatally through the maternal milk. Developmental and
cognitive measurements, along with neurochemical measurements (AChE activity in plasma, red blood cells, heart and
brain tissues), were conducted in both the dams and pups.
Chlorpyrifos had no effect on cognitive functions at any of the
doses and did not cause any developmental effects on the
offspring with the two lower doses, showing that it was not a
selective developmental neurotoxicant in the rat. Only at the
highest dose, which was clearly maternally toxic, were transient effects seen in the pups that were suggestive of delayed
development, and these were attributed to maternal neglect.
The NOEL for maternal and pup toxicity was 1 mg/kg/day.
Furthermore, AChE measurements showed that AChE activity in heart and brain tissues of neonates was 10- to 47-fold
less inhibited than in adults. There was no unique sensitivity of
the neonates to chlorpyrifos, as compared to the mother, when
dose levels and route of exposure were appropriate. Therefore,
empirical evidence suggests that chlorpyrifos is not a selective
developmental neurotoxicant.
Conservatism of the Current RfDs
The RfD values for chlorpyrifos currently used by EPA are
conservative. The NOEL for human plasma butyrylcholinesterase inhibition endpoint, which is the basis for the EPA RfD
values, is a marker of exposure, not an adverse effect. Hence,
EPA RfD values already include a very conservative intraspecies safety factor which is greater than the standard 10-fold
safety factor.
The EPA Federal Insecticide, Fungicide and Rodenticide
Act Scientific Advisory Panel (FIFRA SAP), in June of 1997
(SAP, 1997), also concluded that blood cholinesterases (plasma and RBC) are not involved in cholinergic transmission, and
as such, have no toxicological significance to organophosphate
toxicity. The panel stated that “measured inhibition of cho-
119
linesterase activities in any of the blood fractions are best
regarded as an imperfect mirror of enzyme inhibition in the
true target tissues: brain, neuromuscular junctions, autonomic
ganglia, and autonomic synapses. When, or if, direct measurements at the probable target sites become available, data from
the blood might be under-weighted or even ignored.”
Other regulatory bodies, e.g., the California Department of
Pesticide Regulation (DPR), the governments of Canada and
European Union (EU) member countries, and the World Health
Organization (WHO), base exposure standards on human red
blood cell (RBC) acetylcholinesterase (Canada, EU Countries,
and WHO) or brain acetylcholinesterase in the rat (California
DPR). Therefore, basing the RfD on RBC AChE inhibition
would contribute to global harmonization in the regulation of
cholinesterase inhibitors, and still allow for a significant safety
factor.
Comprehensive studies of the inhibition of AChE activities
in blood, brain, and peripheral tissues after treatment with
chlorpyrifos, at relevant doses in adult and neonatal rats, were
conducted by several groups (Chen et al., 1999; Nostrandt et
al., 1997). The significance of these data in selecting the
toxicological endpoint, the setting of RfD (ADI), and the need
for an additional 103 FQPA safety factor, was assessed. Conclusions from this evaluation are as follows:
(1) There are adequate data on the effects of chlorpyrifos on
blood, brain, and peripheral tissue AChE in both adult and
neonatal rats to establish a conservative RfD that will protect
the health of human adults and children.
(2) RBC AChE is inhibited 12 to118-fold more than brain
or peripheral tissues AChE in adult rats given a single oral dose
of chlorpyrifos, demonstrating that basing the RfD on inhibition of RBC AChE introduces a conservative safety factor for
setting exposure guidelines.
(3) Furthermore, AChE activities in brain and peripheral
tissues of neonates are about 20- to 47-fold less inhibited than
in adult tissues when chlorpyrifos is given to the mother. There
is no unique sensitivity of neonates to chlorpyrifos when dose
levels and routes of exposure are administered in an appropriate manner. Evidence indicates that chlorpyrifos is not a selective developmental neurotoxicant.
Human RBC AChE level is an appropriate and conservative
surrogate enzyme for establishing the chlorpyrifos RfD. This
RfD for chlorpyrifos, based upon RBC AChE inhibition, would
be protective of infants and children.
Exposure Assessment and Risk Characterization
To characterize risk properly, considerations of exposure are
critical. Further, exposure scenarios specific to infants, children, and other potentially sensitive subpopulations need to be
assessed. Results from national market-basket survey, dietary
risk analyses, residential exposure, and biomonitoring studies
demonstrate that exposures of infants and children to chlorpyr-
120
GIBSON, CHEN, AND PETERSON
TABLE 1
Aggregate (Total Dietary and Residential) Exposure to
Chlorpyrifos as Determined by Monte Carlo Probabilistic
Analysis and Biomonitoring
Population
Children (0 to 6 years old)*
Monte Carlo analysis at 99.5 percentile
Children Pesticide Exposure Study (CPES)
Biomonitoring data**
Children biomonitoring data at 100 percentile
Adults*
Monte Carlo analysis at 99.5 percentile
General population biomonitoring data (CDC)***
Adults biomonitoring data at 99 percentile
Adults biomonitoring data at 100 percentile
Aggregate exposure
(mg/kg bw/day)
1.2
1.4
0.46
0.82
1.7
* Shurdut et al., 1998
** Quackenboss et al., 1998
*** Hill et al., 1995
ifos are well below established regulatory guidelines (Bolles
and Cordes, 1997; Byrne et al. 1998; Dixon-White and Tomerlin, 1995; Hill et al., 1995; Quackenboss et al., 1998;
Shurdut et al., 1998; Tomerlin et al., 1995; Vaccaro et al. 1987,
1991, 1993, 1996a,b; Wright and Jackson, 1975; Wright and
Leidy, 1978).
Pursuant to the FQPA, a state-of-the-art probabilistic model
was developed to determine potential aggregate (total dietary
and residential) exposures from all use patterns (Shurdut et al.,
1998). Using this model, estimated aggregate exposure was
low for infants and children, #1.2 mg/kg /day, and was well
below the acute and chronic RfD values for chlorpyrifos of 10
mg/kg and 3 mg/kg/day, respectively (based on the NOEL of
human plasma cholinesterase inhibition and applying at 103
uncertainty factor of intraspecies variation). Comparison of
these results to actual measurements of the primary metabolite
of chlorpyrifos, 3,5,6-trichloropyridinol, made by the Centers
for Disease Control (CDC) in the U.S. population suggests that
the robust exposure database for chlorpyrifos probably characterizes the range of potential exposures to residents (Hill et
al., 1995). Preliminary results from the Child Pesticide Exposure Study (CPES) also suggest that the highest chlorpyrifos
exposures to children, as estimated from urinary TCP analysis,
are less than 1.4 mg/kg/day for chlorpyrifos-equivalent exposures (Quackenboss et al., 1998). Consequently, through this
independent validation using biomonitoring results from the
U.S. population (the children’s sub-population was intentionally selected to represent a highly exposed population), exposures have been characterized with a high degree of certainty
(Table 1).
Decision on the Need for Additional Safety Factor
Based on the SAP decision-making process, and based on a
weight-of-the-evidence evaluation and a reasonable certainty
of no harm, we believe no additional uncertainty factor is
needed for chlorpyrifos to protect infants and children. The
bases for this conclusion are as follows:
(1) comprehensive and complete database for chlorpyrifos
with respect to toxicity and exposure.
(2) Organophosphate-induced delayed neurotoxicity (OPIDN)
was only observed after lethal doses. No evidence of OPIDN
was found when chlorpyrifos was tested in hens in an acute
study at twice the LD50 (100 mg/kg bw), or in a subchronic
study at 10 mg/kg bw/day.
(3) FIFRA guideline reproductive and developmental toxicity studies showed no potential pre- or post-natal effects of
concern.
(4) The recently completed developmental neurotoxicity
study demonstrated that chlorpyrifos is not a selective developmental neurotoxicant.
(5) Many published studies in which chlorpyrifos was administered directly to neonates are not appropriate to assess the
relative sensitivity of infants and children relative to adults,
because the route was inappropriate and much larger doses of
chlorpyrifos were administered than a neonate or infant could
absorb via an appropriate route of exposure.
(6) Results from the national market-basket survey, dietary
risk analyses, and residential exposure/biomonitoring studies
demonstrated that total exposure of infants and children to
chlorpyrifos is low (#1.4 mg/kg/day) and well below established guidelines.
(7) The RfD values for chlorpyrifos used by EPA are conservative. The human plasma cholinesterase inhibition endpoint, on which EPA RfD values are based, is a marker of
exposure, not an adverse effect. Hence, EPA RfD values actually include more than a 10-fold safety factor.
CONCLUDING REMARKS
Risk assessment approaches are crucial to making informed
regulatory and policy decisions about chemicals such as pesticides. Decisions must be firmly based on scientific weight of
evidence with respect to toxicity and exposure, and, especially,
sound science.
Because the SAP’s 5-step process is based on a firmly
established risk-assessment paradigm, its use leads to an objective determination of the need for, or against, an additional
103 safety factor. This approach takes all of the available
information for a chemical into account rather than focusing on
only selected consideration of identified potential hazards. Additionally, consideration of all of the available information for
a particular chemical allows for the identification of inadequate, or missing, data.
Using chlorpyrifos as a case study, we have demonstrated
how scientific evidence of toxicity and exposure can, and
should, inform the FQPA safety-factor decision process. When
the SAP’s scientific weight-of-evidence approach is applied to
DETERMINING THE 103 SAFETY FACTOR
chlorpyrifos, it is evident that the additional 103 safety factor
for children is not needed.
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