Rm. 119, CM #2
1921 Jefferson Davis Highway
Docket Number: OPP-34223
Submitted by Email
Malathion, Docket OPP-34223
Dear Sir or Madam:
These comments are being submitted on behalf of the Natural Resources
Defense Council, a non–profit organization with more than 400,000 members
dedicated to protecting public health and the environment.
NRDC has no direct or indirect financial or fiduciary interest in the
manufacture or sale of the organophosphates forming the subject of these
Organophosphate insecticides are designed specifically to injure the
nervous system, through inhibition of cholinesterase. Malathion is an organophosphate pesticide that has been
widely used on raw agricultural products including edible grains, fruits, nuts,
forage crops, cotton, and tobacco. Malathion
has also been used to control parasites of livestock and domestic animals, by
spraying in and around livestock barns, dairies, poultry houses, food processing
plants, etc. Malathion has
widespread use as a ground and aerial spray to control medfly, the fruit fly,
and mosquito populations. Malathion
is used as a pediculicide in shampoos to treat head lice on children and
adults. Because of its widespread
use and high human exposure, the human and environmental health effects of
malathion and its active metabolite, malaoxon are of great concern.
EPA’s figures suggest that malathion – at 3.4 million pounds of
active ingredient for non-agricultural use -- is the single most widely used OP
non-agriculturally. The fact that
malathion is often applied by aircraft or fogger intensifies concerns about
public health impact of exposure. And,
although some of existing uses are not being supported by EPA and the
registrants, there remains a very extensive list of uses of malathion that EPA
proposes to continue.
NRDC is very pleased with EPA’s decision to cancel certain highly
problematic uses of malathion, most notably: pet formulations and all other
indoor uses (with a few limited exceptions), its uses on livestock, and all
pressurized can formulations. However,
after careful examination of the technical record, NRDC has concluded that EPA
gravely underestimated both the toxicity and exposures for malathion and thereby
underestimated risks associated with many if not all of the uses that will
continue. We therefore call upon
EPA to cancel all uses and revoke all tolerances for malathion.
Specifically, EPA has erred in its decision to downgrade the
carcinogenicity classification of the malathion, overlooked important
limitations of its developmental and neurotoxicity studies in its calculation of
non-cancer concerns, and ignored peer-reviewed literature documenting toxicity
of the malathion metabolite malaoxon. Furthermore,
EPA documents but then ignores
information concerning malathion’s effects on resproductive success in
wildlife (birds and mammals), a serious concern of its own accord and also one
with has important implications for its possible effects on humans. For its
exposure estimates, EPA has also erred seriously,
most notably by completely failing to take into account direct and
intentional exposures when people apply malathion onto their body for lice
control, dismissing the exposures that nursing infants will receive to malathion
in breast milk, and ignoring key uncertainties in environmental transformation
of the chemical to the more toxic malaoxon in the environment, to name only
These malathion study limitations and data gaps on malathion toxicity
and exposure are very clearly beyond the magnitude necessary to justify the
retention of the 10X safety factor under the Food Quality and Protection Act (FQPA).
Indeed, these data suggest the need for an additional safety factor
larger than 10X, in our view of at least 30X.
They furthermore do not support EPA’s decision to drop the legally
required additional 3X safety factor which is triggered when the Agency relies
upon a NOAEL instead of a NOEL. NRDC
thus believes that EPA acted illegally when it calculated its “safe levels”
for malathion. Had the Agency complied with the statute, the use of
malathion would have been eliminated under the terms of the FQPA.
Below NRDC provides detailed comments on our concerns.
Reference will be made to material in the following documents:
Malathion - Report of the Hazard Identification Assessment
Review Committee. December 17,
1997. Abbreviated here as HIARC.
Cancer Assessment Document. Evaluation of the carcinogenic potential of malathion.
Final report. Cancer Assessment Review Committee Health Effects Division,
Office of Pesticide Programs. February
2, 2000. Abbreviated here as CARC1.
Cancer Assessment Document #2. Report of the 12-April-2000 meeting. Evaluation of the
carcinogenic potential of malathion. Cancer Assessment Review Committee Health
Effects Division, Office of Pesticide Programs. April 28, 2000. Abbreviated
here as CARC2.
SAP Report No. 2000-04. Report. FIFRA Scientific Advisory Panel Meeting, August 17-18, 2000.
Set of scientific issues being considered by the Environmental Protection
Agency regarding: A consultation on
the EPA Health Effect Division’s proposed classification on the human
carcinogenic potential of malathion. December
14, 2000. Abbreviated here as SAP.
Human Health Risk Assessment for the Reregistration
Eligibility Decision (RED) Document. Chemical
No. 057701. Case No. 0248.
Barcode D269070. Health Effects Division, Office of Prevention,
Pesticides and Toxic Substances, U.S. Environmental Protection Agency.
September 22, 2000. Abbreviated
here as HHRA-RED.
EPA MUST USE FQPA 10X
Under section 408 of the Food Quality Protection Act (FQPA),
"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."
The FQPA also explains that the Administrator may use a different margin
of safety "only when, on the basis of reliable data" the alternative
will be safe for infants and children.
Organophosphates are designed to be poisonous to the brain
and nervous system, which are substantially alike in humans and insects. EPA has
failed to demonstrate that there are reliable data complete enough to justify
dropping use of the additional FQPA-mandated 10X margin of safety. In
particular, EPA fails to acknowledge that the lack of developmental
neurotoxicity data for individual OPs, from tests using the agency’s
long-validated DNT protocol, constitutes a critical toxicological data gap.
For malathion, EPA also lacks adequate tests of toxicity to the
developing immune system, toxicity to the developing endocrine system, and tests
of toxicity to the function of other organ systems in the post-natal animal
excluding reproductive function. Dropping
the FQPA 10X factor, despite the lack of these data, likely will increase
children’s exposures to these chemicals.
EPA has disregarded results from both a reproductive toxicity study and a
neurotoxicity study, in addition to peer-reviewed literature, that suggest
strong possibilities for increased sensitivity of the developing nervous system
to malathion. These studies are
NRDC strongly believes that EPA is mandated to retain, or
increase, the 10X FQPA safety factor due to the following data gaps, and
information indicating increased susceptibility of the developing CNS to
No reliable data on exposure to malathion from drift, yet,
CDC cites an extensive database of incident reports following drift exposure;
data gap cited in EFED
No reliable data on take-home exposures, drinking water
exposures, and residential exposures from agriculture use; data gap cited in
No data on malaoxon fate, degradation, metabolism, and
mobility; data gap cited in EFED
No reliable data on fate of malathion; data gap cited in
No reliable data on the reproductive toxicity of
malathion; data gap cited in EFED
No data on behavioral and learning disturbances in mammals
and birds; data gap cited in EFED
No data assessment on the use of malathion as a
peliculicide in shampoo, yet data and literature cites incidents and cases of
toxicity due to this application
Toxicity Data Gaps
No developmental neurotoxicology testing (DNT), yet DNT
data call-in issued
No data on inhibition of cholinesterase in infants or
fetuses, in spite of literature and data on the increased susceptibility of the
developing CNS to malathion
No NOEL; the RfD is calculated from a NOAEL
EPA Has Underestimated Exposure risks; Failed to Consider Aggregate Risks
Farmworker Children are an Identifiable High-Risk Group
determining whether to retain the FQPA’s additional 10X margin of safety to
protect children, and in measuring the extent of residential exposure and in
determining aggregate exposure, EPA should acknowledge farmworker children to be
a major, identifiable subgroup of consumers whose unique, increased level of
exposures must be taken into account. These
nearly 1,000,000 children are deserving of protection under the “reasonable
certainty of no harm” health standard under the law.
refusal to retain an additional margin of safety for children in its Malathion
assessment is inconsistent with the need for additional protections for the
fetuses of pregnant farmworker women who may be exposed to Malathion while their
mothers are at work, and the risks facing neonates who are brought to the fields
to accompany their parents due to lack of day care.
These babies, who face exposure to an extremely potent neurotoxin at
vulnerable stages of development are not
employees and may not be disregarded
on the grounds they face an occupational
risk (Farmworker Justice Fund, Comments to the EPA’s Pesticide Docket on the
Preliminary Risk Assessment for Chlorpyrifos, December 23, 1999).
legal analysis submitted by Farmworker Justice Fund to the Pesticides Docket for
the chlorpyrifos risk assessment, has equal applicability to Malathion:
setting, modifying or revoking tolerances, the FQPA directs the EPA to consider,
inter alia, ‘available
information concerning the … effects
of in utero exposure to pesticide
chemicals.’ § 408 (b)(2)(C)(I)(II). In
the case of threshold effects, FQPA also directs the EPA to add an additional
10-fold (or other) margin of safety 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.’
Id. at 408(b)(2)(C)(ii).
In explaining its method of implementing the 10-fold safety factor to the
SAP, the EPA expressly stated that it would not
consider prenatal exposures to the unborn children of pregnant farmworker women
because such exposures are ‘occupational’ and hence, not within the
contemplation of the FQPA. See Presentation for the FIFRA Scientific Advisory Panel by Office of
Pesticide Programs, Health Effects Division on FQPA Safety Factor for Infants
and Children (March 1998). The
statutory language which directs the EPA to consider the effects of ‘in utero’
or ‘pre-natal’ exposures to pesticides makes no exception for occupational exposures. Nor could such an exception make sense since it is patent
that a fetus or unborn child cannot work.
“In an analogous context, the California Supreme Court has held that a child, who was injured in utero when his pregnant mother was exposed to carbon monoxide at work, could not be prevented from filing suit in tort by the workers compensation bar, which prohibits an employee from suing his or her employer. Synder v. Michael’s Stores Inc, 16 Cal.4th 991, 945 P.2d 781, 68 Cal.Rptr.2d 476 (1997). The Court dismissed the notion that the unborn child could be deemed an ‘employee’ as ‘wholly without merit.’ The Court also noted that every other court to consider this question - except one - had reached the same conclusion (and the only exception was a lower California court whose decision was effectively overruled by the Synder case). Since an unborn child cannot be an ‘employee,’ its pesticide exposure cannot be ‘occupational.’
Thus, any prenatal exposure to the fetuses of farmworkers
must be considered in the determination to modify or eliminate the additional
FQPA 10-fold margin of safety for infants and children
Drift and Take-Home Exposures to Organophosphates
EPA fails to estimate residential exposures for many
organophosphates when there are no registered residential uses. Many OPs,
including malathion, are also applied aerially, and air drift of pesticide
residues into households and onto lawns should be anticipated, and taken into
consideration in the risk assessments. Drift
from terrestrial applications of OPs to fields may also occur.
The Malathion Human Health Risk Assessment does include an evaluation of
spray drift from mosquito control applications and from boll weevil eradication
applications. Assessment of these exposure pathways results in highly suspect,
very high MOEs for cholinesterase inhibition, over 1000 even for inhalation
pathways (for example, p. 61).
However, another section of the Assessment (pp. 39-40)
provides a view of the real-world effects from spray drift.
For example, in Florida in 1998, Malathion was applied for medfly control
to an area with a population of 132,000. Thirty-four
(34) cases were classified as probable, and 89 as possible pesticide-related
illnesses resulting from the application. Most
of the effects were presumed, to be due to the irritant/allergic effects
of malathion bait, rather than cholinesterase inhibition.
Nonetheless, the identification of over 100 persons who were harmed from
this spraying means that EPA cannot assure a “reasonable certainty of no
harm” from this use. At minimum,
EPA should be requiring less harmful formulations, methods of application, or
chemicals for medfly control. This
situation also demonstrates the pitfalls of regulation via statistical
techniques: The 123 illnesses
represent 0.09% of the population in the area sprayed, and become
“disappeared” if evaluation stops at the 99.9th percentile.
Moreover, it is reasonable to assume that only a small percentage of
affected persons sought medical attension, so reported cases represent the tip
of the iceberg of affected individuals.
Children and others experience substantial potential
exposures through drift from such spraying, and through take-home exposures
when, for example, pesticides are exhaled from parents' lungs or brought home on
boots, work clothes, etc. (Mott, L, Our
Children at Risk: The 5 Worst Environmental Threats to Their Health, Natural
Resources Defense Council, San Francisco, CA, 1997.)
Pesticides used on lawns, gardens and nearby farms end up in soil and are
tracked into the home on shoes and pets. (Mott, L.)
One common lawn herbicide, 2,4-D, has been found to persist in carpet
dust up to a year after lawn application. (Nishioka,
M. et al., "Measuring Transport of Lawn Applied Herbicide Acids from
Turf to Home: Correlation of Dislodgeable 2,4-D Turf Residues with Carpet Dust
and Carpet Surface Residues," Env. Sci. and Tech. 30(11), pp. 3313-3320,
1996.) For one OP, methyl-parathion, for example, 34% of original residues
remained in clothes even after 10 launderings—a level high enough to kill
insects and present a health risk to humans. (Solomon, G, Trouble
on the Farm: Growing Up with Pesticides in Agricultural Communities, 1998, citing
Laughlin, J, Gold R, Laundering Pesticide Contaminated Clothing, University of
In certain "sentinel" populations, such as
farmworker children who live in a pesticide-rich environment, these non-dietary
sources may account for most of a child’s exposure regardless of whether there
is registered indoor use. Reports
in the medical literature describe numerous preventable illnesses and deaths
among children with such “take-home” exposures. NRDC’s report, Trouble on the Farm, documents the scientific evidence supporting
the potential for take-home exposures from organophosphates, even when not
registered for residential use (this report is hereby incorporated by reference,
and was an attachment with NRDC’s comments on malathion, July 27, 2000, OPP#34223-L010).
These exposures are particularly important for children given their
greater potential susceptibility, hand-to-mouth behavior and other behaviors in
Under FQPA, take-home exposures for organophosphate
chemicals at least must be estimated. EPA’s
failure to incorporate these real-life exposures into its risk assessments will
tend to result in final risk estimates that are less than health-protective.
If data are lacking to quantify such exposures, the FQPA allows for the
use of an additional 10X margin of safety to assure that use of the chemical is
consistent with a reasonable certainty of no harm to children until more precise
data can be generated.
Drinking Water Exposures
EPA’s preliminary OP risk assessments often fail to
assess drinking water exposures. Drinking
water is an important part of the diet, and for infants especially may be a very
significant constituent of the diet on a weight–adjusted basis.
No dietary risk assessment can be complete without drinking water
Under FQPA, drinking water exposures to organophosphates
(through both ingestion and inhalation and dermal absorption from hand-washing
and showers) must at least be estimated. "Refinement" of drinking
water data in a risk assessment may be an appropriate long–term goal, but it
is scientifically unjustified for EPA to intentionally circumscribe the scope of
the preliminary risk assessment by ignoring non–dietary exposures in the
interim. Where EPA lacks drinking
water monitoring data for specific chemicals, it should make quantitative or
qualitative estimates and be frank in its description of both the assumptions
and the limitations of the data.
When EPA fails to incorporate real-life drinking water OP
exposures into its risk assessments, it will tend toward risk estimates that are
less than health-protective. If
data are lacking to quantify drinking water exposure to individual OPs, the FQPA
mandates the use of an additional 10X margin of safety to assure that use of the
chemical is consistent with a reasonable certainty of no harm to children until
more precise data can be generated.
Inclusion of drinking water exposures into an aggregate
exposure assessment is critical for two additional reasons.
First, EPA decision–makers should be presented with a risk assessment
that reflects the entire range of real–life exposures to the chemical in
question. Second, because exposure
to OP-contaminated drinking water will tend to add to the estimated risk, its
inclusion in the preliminary risk assessment is necessary to demonstrate, in the
most transparent way, the urgency of taking immediate steps to reduce that risk.
Exposures for Registered Residential Uses
Risk assessments for OPs with registered residential (read
non-food) uses have generally shown exceedences due to those uses. Given the
high risks from residential exposures, and given the often unacceptable dietary
exposures, continued use of OPs for residential purposes cannot be justified.
The Malathion Human Health Risk Assessment identifies
several residential exposure scenarios with unacceptable risks.
Mixer/loader/applicator scenarios with unacceptable risks include
application with a low pressure handwand, and application of dust with a shaker
can (p. 48). Postapplication
scenarios with unacceptable risks include exposures of adults and children to
treated turf; and exposures to residues on vegetable/fruit gardens, fruit trees,
ornamentals, and “pick-your own” strawberries (p. 50).
Use of Malathion as a Pediculicide
A case study suggested fetal deformities following
maternal exposure to malathion as a head lice shampoo (Lindhout and Hageman,
1997), suggesting, along with other incident reports and literature, that this
is an exposure route of very great concern.
The Assessment (HHRA-RED, p. 1) reports that it did not include a non-FIFRA
malathion use as a pharmaceutical, regulated by FDA, to remove head lice and
eggs. EPA says it is developing a
process to determine if these uses should be considered in EPA risk assessments.
Since pharmaceutical approval requires a determination of both safety and
efficacy, one would expect that FDA had already conducted its own risk
assessment. It should therefore be
straightforward to merge the FDA analysis into EPA’s aggregate assessment.
At a minimum, the process that EPA develops must guard against the use of
FDA regulation as a loophole that removes pesticide exposures from EPA
assessments. Either EPA must work
with FDA to ban the use of malathion as a pediculicide, or EPA must estimate or
represent this use in its aggregate risk assessment.
If no data are available, EPA must retain the 10X FQPA safety factor.
Residential Exposure from Agriculture Uses
These comments treat this topic in greater detail in the
following section, but it seems appropriate to point out that EPA cannot assure
the required “reasonable certainty” of no harm to those living in
agricultural areas when it systematically fails to assess what may be some of
their greatest sources of exposure. EPA’s
practice has been to omit estimating residential exposures for organophosphates
which have no registered residential uses.
This is an unscientific approach that ignores existing data as well as
what we know about the real world. It
is also less than protective of public health.
Residents of agricultural areas may experience
significantly greater exposures to pesticides than their urban counterparts.
These highly-exposed populations, especially children in agricultural
areas, must be protected when EPA decides allowable food exposures.
Registered, non-residential uses of many OPs can and should be expected
to result in residential exposures. For example, OPs applied aerially must be
assessed not only for their effects on pilots, but on the people living below
the plane and affected by pesticide drift or sloppy application.
EPA has stated in previous risk assessments (e.g. for ethyl parathion)
that it “remains concerned that existing buffer zones (100 feet from
buildings, public roads etc.) may not be adequately protective and would not
prevent ethyl parathion exposure to bystanders” during aerial spraying.
EPA’s continued decision to not incorporate these real–life exposures
into its OP risk assessments will only serve to drive final risk estimates that
are inaccurate, unscientific and less than health–protective.
EPA must also consider and build into its OP risk
assessments the fact that worker risks may "spill over" to the
families of workers and to fetuses that workers may carry on and off the job.
For example, pregnant women working or living on or near farms may very
well have OP exposures that clearly fall within the purview of the FFDCA section
408 aggregate safe exposure requirement—particularly (but not exclusively)
when the exposures occur off the work site due to take–home/drift exposures.
EPA policy appears to be to apply an additional FQPA 10X margin of safety, when
applicable, only to consumers of food crops and not to exposed workers and their
families. Given the certainty of
drift and take–home exposures, this policy must be reexamined.
Percent of food treated calculation in acute risk
FQPA specifically authorized EPA to consider the percent
of crop treated (%CT) “when assessing chronic
dietary risk . . . only if the Administrator” makes four specific findings
about data reliability. FQPA § 408
(b)(2)(F). This explicit statement
permitting the use of %CT calculations in estimating chronic dietary risks gives
rise to the logical conclusion that Congress
did not intend for EPA to use %CT in
estimating acute dietary risk.
This concusion makes sense since Congress may well have assumed that, in
assessing chronic dietary risk, the likelihood that a person will experience
harm from chronic exposures over time could be affected by the overall
percentage of that crop treated with that chemical.
It also makes sense that Congress realized, that for acute
harms resulting from a single exposure, it is irrelevant whether a large or
small percentage of that crop was treated with that pesticide.
Any amount of a crop treated at
a level causing acute harm could not be characterized as assuring a
“reasonable certainty of no harm,” making it completely inappropriate to use
%CT in assessing acute dietary risks.
With malathion, the Human Health Risk Assessment reports
that acute dietary risk was considered acceptable after Tier 1 analysis, which
assumed reassessed tolerance values and 100% of the crop treated (p. 29).
EPA’s assessments for OPs thus far have failed to assess
aggregate dietary and non–dietary exposures, even though specifically required
by the FQPA. The Human Health Risk
Assessment for Malathion does include
an assessment of aggregate exposure (pp. 60ff), but under procedures producing
results of limited usefulness. First,
the Assessment excludes from analysis home garden residential uses, which on
their own accord produce risks that are unacceptable. This approach seems reasonable only if EPA plans to
immediately prohibit all such uses. Otherwise,
aggregate risks from malathion and cumulative OP risks are drastically
understated, and the agency’s assessment cannot be considered valid.
Once the offending residential uses are excluded, EPA
conducts only a limited “aggregate” assessment for exposures from food,
public health mosquito control, and spray drift from boll weevil uses.
EPA wholly ignores the use of malathion as a pediculicide in shampoos.
These exposures must be considered more comprehensively.
The contribution from drinking water is evaluated under an
approach designated Drinking Water Level of Comparison (DWLOC).
Risks from dietary and the spray drift pathway are aggregated, and
equivalent residue levels in drinking water are identified which would fill the
aggregate “risk cup” to the maximum acceptable level.
While it appears that malathion levels in groundwater from monitoring
data are below the DWLOC, the precise contribution to the risk cup from residues
in water is not clearly stated, leaving this determination as an exercise for
the interested reader. A clearer
description of the potential contribution from water is necessary for a
meaningful determination of the relative contributions to risk from different
pathways, and to evaluate the effectiveness of potential risk reduction measures
for aggregate and cumulative OP risks. Moreover,
as noted above, it is not clear that the much higher toxicity of malaoxon
compared to the parent compound has been incorporated into exposure from water
or other pathways.
EPA’s aggregate exposure
assessments should include residential exposures due to air drift and migration
of contaminated soil, especially in agricultural areas, residential exposures
from registered uses (including home, school, turf and pet uses), residential
“take-home” exposures to families of those directly exposed to the OP
through its agricultural uses, as well as exposures from uses that do not
conform with the label, where there is an indication that these uses occur, as
When lacking actual data on any
these various sources of non-dietary exposure, EPA should not simply assume that
the particular route of exposure is unimportant or nonexistent, as is often done
currently. Rather, the risk
characterization should clearly note that failure to include all possible routes
of exposure will tend to bias final estimates of aggregate risk so that they may
understate rather than overstate true risks; in other words, risk estimates tend
to be less rather than more protective of public health.
Moreover, when, as in the case of malathion, there are not actual data to
confirm the absence of exposure to a pesticide across any particular route--e.g.
contaminated drinking water, indoor air, household surfaces etc.—EPA should
retain the additional tenfold FQPA safety factor to account for this lack of
complete exposure data.
EPA Has Not Adequately Considered Toxicology Data Gaps and Data
Indicating Increased Susceptibility of Children
On the basis of an unprovable hypothesis/explanation, and
without any supporting data, EPA has decided to ignore the results of a study
that shows that young rats may be more susceptible to the toxic effects of
malathion than adults. Specifically,
it is disregarding the two-generation reproduction study with Sprague-Dawley
rats (MRID 41583401). This study
determined the parental systemic toxicity NOAL to be 5000 ppm (394/451 mg/kg/day
in M/F) and the LOEL to be 7500 ppm (612/703 mg/kg/day in M/F), based on
decreased body weight. For
offspring toxicity, the NOAL was 1700 ppm (131/135 mg/kg/day in M/F), and the
LOEL was 5000 ppm (394/451 mg/kg/day in M/F), based on decreased body weight.
Thus, the offspring NOEL was one-third the parental NOEL in this study.
NRDC notes that neither adult nor offspring cholinesterase was measured (MRID
41583401) (HIARC, p. 15; 25/OPP#34223). The
EPA discounts this study with a scientifically unsupported explanation that the
pups in the study “likely” consumed twice the diet per unit body weight as
the adults during nursing, and therefore likely had double the intake of
malathion (p. 15, ibid). This leads
the Agency to assert that the differences in treatment effects are due to
differences in dosing rather than sensitivity to malathion.
But, no attempts were made to measure malathion in the milk and no
attempts were made to more exactly quantitate the total intake of malathion in
the pups. Furthermore, no attempts
were made to statistically correct for this presumed confounder.
To the contrary, the study results are simply reported, and then
dismissed out-of-hand. Even if the explanation were correct, a double-intake
of malathion does not explain a triple-increase in susceptibility.
Most importantly, even if it were true that the results
seen in this study were due to dosing instead of differential sensitivity, NRDC
is perplexed why EPA does not concern itself with the human exposure pathway of
malathion through breastmilk. As
with the animals, nursing humans face a likely scenario of being exposed to
malathion in both mother’s milk and food/their environment during the course
of their early years. Such a
“double dosing” scenario is not developed by EPA in its setting of safe
levels for malathion. Maybe this is
an oversight, and should be corrected!
A review of the literature, published in peer-reviewed
journals, and cited in EPA’s own documents (HIARC, p.16) provides much
additional support for the increased susceptibility of the young to
cholinesterase inhibitors, including malathion. Wyttenbach and Thompson (1985) demonstrated a dose- and
age-dependent susceptibility to malathion in chicks, doubling for each doubling
of dose, tripling for each 24 hr less age at exposure.
A case study suggested fetal deformities following maternal exposure to
malathion as a head lice shampoo (Lindhout and Hageman, 1997).
A study of the effects of malathion in suckling albino rats demonstrated
that 1-day old pups were nine times more susceptible than 17-day old pups, and
four and five times more susceptible than 12- and 6-day old pups, respectively
(Mendoza, 1976) (Jan. 29, 1999 letter from Dr. Dementi to Dr. Swentzel).
Furthermore, there is a recent study in the open
literature, by Mortensen and collegues, not cited by EPA (Toxicol, 1998. Vol.
125; 13-18) which presents a developmental profile of cholinesterase activity in
the male rat brain. These
researchers demonstrate that the increased susceptibility of the immature
nervous system to cholinesterase inhibitors is due primarily to a reduced
activity of acetylcholinesterase (AChE), which constitutes 90% of the total
cholinesterase in the brain. As the
brain matures, the activity of AChE increases, and the animal less vulnerable to
the damaging effects of the organophosphate pesticides.
This study not only confirms the observations of many other researchers,
but provides a scientific explanation for the reduced tolerance of children to
delayed neurotoxicity study
In an acute delayed neurotoxicity study (MRID 40939301),
hens were given two doses of malathion, administered by gavage.
The first dose was 1.3X the oral LD50 (775 mg/kg), and the second dose
was 1.5X LD50 (852.5 mg/kg). NRDC
charges that this study is utterly inadequate to properly assess neurotoxicity
end points of concern when evaluating the protection of human health.
The doses are so high, mortality would preclude any evidence of toxicity.
The study claims that the only observed clinical effects were due to
inhibition of cholinesterase. Of
course! This is considered a
treatment-effect! The study claims that no further
treatment-related effects were observed by either necropsy nor
histopathology. This is hard to believe, since only 14/60 hens survived the
study! What did the other 46 hens
die of, if it wasn’t treatment-related? And,
were no abnormal behavioral signs observed, prior to the 46/60 hens dying?
NRDC is unimpressed with this study and EPA’s conclusions (reported in
HHRA-RED, p. 18) and, as a consequence, concludes that EPA has a serious data
gap on its hands with regards to properly assessing the neurotoxic potential of
Lack of DNT; data gap and FQPA
The Human Health Risk Assessment for Malathion (p. 21)
notes that the FQPA safety factor is removed (reduced to 1X) due to no increased
sensitivity following pre- and post-natal exposures; negative neuropathology;
and the toxicity database being complete with no significant data gaps. At the
same time, the Assessment (p. 9) notes that the Agency recently issued a Data
Call-In for a developmental neurotoxicity study for neurotoxic pesticides,
including Malathion (p. 9).
In a written statement, Dr. Dementi (letter of Nov. 8,
2000; 13/OPP#34223A) sums up the data gap for malathion as follows:
After much expression of
differences of opinion at committee meetings, the following have now become
additional testing requirements that remain to be satisfied: a)
subchronic inhalation study, b) developmental neurotoxicity study, c)
cholinesterase assessments of young versus adult animals in connection with the
developmental neurotoxicity study, d) additional cholinesterase testing in the
dog. The incomplete status
of the data base as evidenced by these outstanding studies, further supports
retention of the FQPA 10X safety factor for the protection of infants and
children as required by Congress.
In asserting that it has a “complete” toxicology
database with respect to FQPA requirements, EPA means that data have been
submitted from both two–generation reproductive toxicity and prenatal
developmental toxicity studies, and that these studies indicate no increased
sensitivity to in utero and/or
postnatal exposure. This is an
insufficient basis for dropping the child–protective FQPA safety factor for
Dr. Susan Makris noted in her December 1998 presentation
to the FIFRA SAP that the Agency’s two core studies in developing animals are
not the most sensitive measures available to the Agency for assessing
pre–natal or postnatal developmental effects — particularly for assessing
developmental neurotoxic effects of special relevance to the organophosphates. (Makris
et al., A Retrospective Analysis of Twelve
Developmental Neurotoxicity Studies Submitted to USEPA Office of Prevention,
Pesticides and Toxic Substances (OPPTS), 11/12/98)
For eight of the nine pesticides reviewed, Dr. Makris found that the NOEL
from developmental neurotoxicity testing was lower than the fetal NOEL from the
EPA’s "core" test of prenatal development toxicity; in addition, the
offspring NOELs from developmental neurotoxicity testing were lower than
offspring NOELs from the two–generation studies of reproductive toxicity for
six of nine pesticides assessed.
These results strongly suggest that developmental
neurotoxicity (DNT) testing is essential for pesticides, not only as a measure
of toxicity to the developing brain and nervous system, but also as an often
more sensitive measure of developmental and reproductive effects generally.
Research by Ulbrich and
Palmer supports this conclusion. It
shows that for 28% of 85 drugs the behavioral effects detected using tests of
developmental neurotoxicity were either equal to the LOAELs detected on other
tests of developmental toxicity, or were the only adverse effects detected at
any dose. (Ulbrich B, Palmer, AK, Neurobehavioral aspects of developmental
toxicity testing. Environ.
Health Perspect. 104 (Supp. 2), 407-412, 1996). This study was cited by EPA’s 10X Task Force in
recommending that "developmental neurotoxicity testing be included as part
of the minimum core toxicology data set for all chemical food–use pesticides
for which a tolerance would be set." (USEPA,
Toxicology Data Requirements for Assessing
Risks of Pesticide Exposure to Children’s Health (draft), 10X Task Force,
11/30/98, p. 11) Former Assistant
Administrator Lynn Goldman, M.D., highlighted this recommendation in presenting
the Task Force report to the SAP in December 1998.
OPP’s acknowledgment that developmental neurotoxicity
testing is important enough to amend 40 CFR Part 158 requirements makes it clear
that these data are necessary for a complete toxicological database. Instead, in
its draft 10X policy, EPA has made the tautological proposal that it will
consider DNT data to be part of the “core” toxicology database only after
the Office of Management and Budget has approved changes to 40 CFR Part 158 and
they become final, and only after a registrant has had “sufficient” time to
conduct these tests. EPA’s
tautology starts with the presumption that one must evaluate the completeness of
the toxicology database from the perspective of the pesticide manufacturer.
EPA’s proposed policy says, in other words, that as long as a pesticide
manufacturer has met current legal requirements, there cannot be a determination
that the toxicology database is incomplete.
Not only is this approach unscientific, it ignores the National Research
Council’s finding that EPA’s “current core toxicity testing protocols do
not, for the most part, adequately address the toxicity and metabolism of
pesticides in neonates and adolescent animals” — i.e. are not complete with
respect to infants and children.(NRC, Pesticides in the Diets of Infants and
Children, National Academy Press: Washington, D.C., 1993, p. 4.)
This finding was the basis of the NRC’s recommendation that an
additional 10X safety factor be added; the NRC’s recommendation was enacted
into law by FQPA.
EPA’s approach runs counter to the intent of the FQPA.
The Food Quality Protection Act required that the completeness of the toxicology
database be evaluated with respect to the law’s health standard— the
standard that this database provide a reasonable certainty of no harm to infants
and children. As noted, EPA has
admitted that DNT testing is necessary to provide a reasonable certainty of no
harm to children. Why else plan to
make it a core requirement for registration of new pesticides?
The absence of a completed DNT study for an organophosphate insecticide
therefore compels the conclusion that data are incomplete.
On August 6, 1999, EPA announced its intent to “call
in” data from acute, subchronic, and developmental
neurotoxicity studies from the registrants of 140 already-registered neurotoxic
pesticides. (Federal Register: August 6, 1999, Volume 64, Number 151, page
registrants will be issued Data Call-In Notices in phases, with registrants
expected to submit the studies within 2 years of the DCI.
To our knowledge, only the first phase of the DCI has been carried out,
which on September 10, 1999 called-in data for 34 cholinesterase-inhibiting
While we applaud EPA’s issuance of a DCI for acute,
subchronic, and developmental neurotoxicity data, we consider this issuance to
constitute an admission that these data are necessary for a complete
toxicological database. For cholinesterase-inhibiting organophosphate insecticides,
in particular, registrants have had ample opportunity to perform this testing in
the past. OPs are specifically
designed to be toxic to the nervous system, so the importance of all
neurotoxicity testing should have been anticipated by registrants. Moreover, this DCI comes ten years after EPA published a
validated DNT protocol, fourteen years after DNT testing was validated in the
scientific literature, and up to forty years after individual OPs were first
registered for use. EPA should
therefore retain the additional FQPA 10-fold safety factor while waiting for
results from these tests, and while these neurotoxic pesticides remain in use,
to assure that EPA’s regulatory decisions are protective of children.
RfD BASED ON NOAEL
the National Research Council/National Academy of Sciences report Pesticides
in the Diet of Infants and Children and the FQPA language based on its
findings, clearly state the purpose of the additional, child-protective FQPA
tenfold safety factor. The report
of the House Committee on Commerce further clearly states that its intent is for
all safety factors to be applied to the NOEL, or No Observed Effect Level.
(House Committee on Commerce Report 104-669, Part 2, at 43, presented to the
House on July 23, 1996) However, in
the case of malathion, the Human Health Risk Assessment (p. 21) reports that
toxicology endpoints selected were NOAELs for dietary and dermal exposure and a
LOAEL for inhalation exposure. The
use of the LOAEL was accompanied by an additional 10X uncertainty factor, but
the legally required safety factor is not added when using the NOAEL rather than
a NOEL for determining the RfD.
and LOELS are drawn from only a limited number of dose levels, and the
difference between them in a single animal test can be tenfold or more.
By itself, therefore, the use of a LOEL rather than a NOEL to derive an
RfD may, in effect, largely negate the additional protections intended for
children in the FQPA through numerical sleight of hand.
As with NOEL versus LOEL, the difference between a NOEL and a NOAEL can
be as much as tenfold or more, again potentially negating the effect of the
additional protection intended by Congress on passage of FQPA.
EPA’s RfD for malathion is based on a developmental
toxicity study in rabbits (MRID 40812001).
In this study, the maternal and developmental NOAEL and LOAEL were
determined to be equal (25 and 50 mg/kg/day, respectively).
Neither maternal nor fetal cholinesterase levels were measured, and NOAEL
and LOAEL levels were based on an increased incidence of mean resorption sites
per dam. The NOAEL was determined
to be 2.4 mg/kg/day, and the chronic RfD 0.024 mg/kg/day (Apr. 26, 2000 revised
NOAEL derivation). Nowhere is a NOEL determined, and nowhere is an additional
safety factor applied. An
additional 3X safety factor should be imposed upon the existing chronic RfD in
the absence of a definitive NOEL for cholinesterase inhibition.
Further, Dr. Dementi points out in comments that there is reason to
believe rats may be less sensitive than humans to malathion, due to the presence
of plasma carboxylesterase in rats. (Nov. 8, 2000; 13/OPP#34223A).
This further supports the additional 10X FQPA safety factor, in addition
to the 3X uncertainty factor required when using a NOAEL for RfD determination.
Thus, a 30X uncertainty factor is appropriate.
99.9th percentile policy
The law does not allow EPA to
sacrifice hundreds or thousands of children who may exceed the reference dose.
The burden is on EPA to prove with a reasonable certainty that no
children will be harmed under the tolerance set for the pesticide chemical
residue. By any interpretation, if
the best evidence suggests that hundreds or thousands of children will exceed
the reference dose, then EPA cannot find a reasonable certainty of no harm to
infants and children and the Agency may not issue a tolerance at that level.
EPA’s usual approach for
OP’s, described as a “highly refined” Monte Carlo risk analysis regulating
at the 99.9th percentile, however, seeks to mask the fact that at
that level some 24,000 children under six years old would be predicted to exceed
the RfD every day, based on the best information available to the agency.
No reading of the statute will support any approach that allows hundreds
or thousands of children to exceed the reference dose.
With malathion, EPA’s approach is substantially less
protective, and in essence condems hungreds of thousands of children to
exceeding the RfD. This is an
unacceptable, unjustified, outrageous departure from past EPA policy.
Acute dietary risks were reported for individuals estimated to be at the
95th percentile of exposure, based on tolerance values and 100% crop
treated. The highest exposures on this basis were 38% of the acute PAD
(population adjusted dose) for the most highly exposed age group (Risk
Assessment, p. 28.) Risks to people
at even higher levels of exposure (e.g. people whose exposures are higher than
any other 95 people in the population, for example) were not reported.
This method of risk assessment is negligent, irresponsible, and allows an
unacceptable risk for people in the highest exposure group.
CLASSIFICATION OF MALATHION AS A CARCINOGEN
Change in Classification
EPA has undertaken two recent reviews of the
carcinogenicity of malathion, first with a CARC1 review (Feb. 2, 2000) and then,
three months later, with a CARC2 review (April 12,2000).
Whereas CARC1 classified malathion as a “likely human carcinogen” by
all routes of exposure, CARC2 downgraded the chemical as only
“suggestive…but not sufficient evidence to assess human carcinogen
potential”. Despite concerns
subsequently expressed by some members of EPA’s Human Health Risk Assessment
Committee and SAP on this topic, the Agency proceeded to follow the advice of
its CARC2 review. As a practical matter, this downgrading in classification
means that malathion will not be regulated as a carcinogen following a low-dose
linear extrapolation model. However,
the scientific basis for CARC’s downgrading of the carcinogenicity of
malathion is fundamentally flawed. It
relies on an unjustifiable decision to ignore tumors at high doses and
completely overlooks the fact that, in any case, tumors appear at lower doses as
The 1986 cancer risk assessment guidelines state that EPA
takes conservative (public health protective) default positions regarding the
interpretation of toxicologic and epidemiologic data. Cancer risks are assumed to conform with low dose linearity.
The guidelines states that mode-of-action information may be considered
as a basis for departing from the assumption of linearity, but, the database on
mode-of-action must be rich and able to both describe the sequence of key events
in the putative mode-of-action and demonstrate it experimentally (66 Fed. Reg.
6976, 7021[Jan 22, 2001]). In the
case of malathion, this database would not be considered sufficient; there is an
even greater paucity of information regarding mode-of-action of the active
metabolite, malaoxon. There is
nothing in the Draft Cancer Guidelines (July, 1999) which would suggest any
deviation from the understanding that cancer risks are assumed to conform with
low dose linearity, and that elucidation of mode-of-action is a data-rich
CARC1 clearly was concerned about the carcinogenic
potential of malathion; it
recommended that a linear low-dose extrapolation approach be used (Q1*), based
on the most potent unit risk, which was female rat liver adenoma and/or
carcinoma combined tumor rates at 1.52 x 10-3 in human equivalents.
The change in classification of malathion by CARC2, however, was made
new data, raising questions about the basis for such a radical change in the
regulatory basis for this chemical. NRDC notes that serious concerns about this
unjustifiable change were raised by one of EPA’s own experts, Dr. B. Dementi,
Senior Toxicologist, HIARC-Health Effects Division, Dr. H. Needleman, Professor
and MD, FIFRA SAP member (Letter of Sept 20, 2000; 11/OPP#00670-1), and the
California EPA (Letter of July 18, 2000; 12/OPP#00670-1), a state whose high
agriculture production and problems with medfly infestation has triggered very
tangible concerns about safe exposures. The very fact that this
change in classification was made: (1)
without new studies, (2) following guidelines which are in a DRAFT stage only,
(4) without complying even with those draft cancer guidelines, and (3) in a
manner that would no longer requiring a low-dose linear extrapolation model, suggests:
a rather arbitrary decision-making process of dubious scientific quality, a
serious flaw in the draft guidelines, and a move away from the protection of
Evidence of Carcinogenicity
The mouse study (MRID43407201) showed incidences of
hepatocellular tumors were increased in treated mice of both genders.
Statistically significant increases in liver carcinomas, and combined
adenomas/carcinomas in male mice were seen at 100 and 8000 ppm in males, and at
8000 and 16,000 ppm in females (CARC1, p. 3).
The CARC1 committee decided that the liver tissue from male mice should
be re-evaluated by the Pathology Working Group (PWG), based on “the
statistically significant increases in hepatocellular tumors in male mice at low
(100 ppm), mid-high (8000 ppm) and high (16000 ppm) doses, but not at the
mid-dose (800 ppm), and the apparently low tumor incidences in the concurrent
control (male) mice.” (p.3). In a
critical, unjustified, and unjustifiable change in diagnosis, the PWG downgraded
half the tumors from carcinomas to adenomas (CARC1, p. 6), and thereby paved the
way for SAP to call the observations “benign”, unfairly excluding adenomas
(SAP, p.11). Comments submitted on
this matter to the Agency by panel member Dr. Needleman explain that, “The
post hoc revision of diagnoses, examining only the positive or conflicting
diagnoses, and with the knowledge of the final conclusions is inferior science,
and cannot be rectified by blinding judges” and concludes that the procedures
used by the PWG not simply inferior
science; it is not science at all.” (Needleman letter, ibid). Clearly EPA erred in accepting this post-hoc reassessment of
Compounding this first error in judgement is the fact that
the mouse study in question did not progress for the full two years standard
under EPA protocol, but was truncated at 18-months.
EPA is surely aware that adenomas often progress to carcinomas over time.
Further, a 1978 NCI study reported increased incidences of liver tumors
in male mice at 16000 ppm malathion (CARC2, p. 12), suggesting that the
progression from adenoma to carcinoma in these animals is to be expected. It is
thus possible, even likely, that any bona fide adenomas counted in this study
would have progressed to carcinomas over an additional six months.
These concerns were pointed out to the panel in comments by Dr. Dementi
(Jan 18, 2001), and California EPA, but were also ignored.
NRDC agrees with these EPA scientists; adenoma
findings are indicators of carcinogenicity, and must NOT be dismissed!
NRDC has additional concerns about EPA’s decision to
overlook liver tumor increases in male and female mice at the doses of 8000 and
16000 ppm malathion exposure. Although
CARC2 discounted these tumors because they occured in “in the presence of
severe toxicity”, toxicity was defined as severe cholinesterase inhibition
(CARC2, 2000, p. 12). This argument
was not accepted by the SAP, which stated that, “using AchE levels
to define an excessive dose has no biological basis”.
NRDC agrees with the SAP (SAP, p.12).
Note also that in any case, 23%
of the combined adenoma/carcinomas in mice treated with malathion were observed
in the lower two doses! Clearly,
these studies were positive for cancer findings, even at low doses.
Thus, NRDC strongly disagrees with EPA’s conclusions
that liver tumors occured only at “excessive” doses (HHRA, p. 14, 21).
This conclusion is inaccurate, it is in disagreement with the previous
conclusions of the CARC2 Committee, and it is without sound scientific basis on
which “excessive” doses were determined.
In fact, written comments by California EPA, state that “... concerns
warrent a re-thinking of the determination that “excessive doses” justify
discounting the tumor response data”. In
this letter, the State appeals to the US EPA’s own guidelines to support its
F344 rat study
Similar arguments about excessive dose were made in the
case of the increased incidence of liver tumors observed in the F344 Rat study,
(MRID 43942901) (HHRA-RED, p. 14, 21). That
is, that tumors are seen only in high doses, and that these high doses are
excessive. Again, although the
occurance of liver tumors in female F344 rats were similarly limited to adenomas
at the high doses, a glance at the data reveals that a
full 38% of adenomas occurred in the lower dose range!
This was pointed out in Comments by Dr. Dementi (Jan. 18, 2001; 17/OPP#00670-1),
and was considered acceptable by CARC1 (Feb. 2000, p. 11). The CARC1
Committee “concluded that the incidence of liver tumors at the 50 and 500 ppm
dose levels provide suggestive evidence of carcinogenicity and cannot be
discounted. The Committee also concluded that the liver tumor incidences
at 6000 ppm and at 12,000 ppm (although considered excessive doses) provide
positive evidence of carcinogenicity” (CARC1, p. 11).
NRDC, after review of the study data and docket information, agrees with
this conclusion, and believes that the liver tumor data are substantial and
scientifically sound. Thus, a low-dose extrapolation model of carcinogenicity is
A second component of the downgrading of malathion’s
carcinogencity classification is EPA’s decision to discount nasal tumors that
were observed in rats. EPA
questioned whether these tumors were a result of malathion exposure or an
artifact. NRDC believes that in the
face of uncertainty in interpreting these tumors, EPA should have erred on the
side of safety and considered them significant.
The SAP’s conclusion “while it is unlikely that these
two tumors were related to malathion treatment, it cannot be unequivocally ruled out” (SAP, p. 16) supports NRDC’s
view that EPA should have taken a more precautionary approach in its application
of this data to a decision on malathion. This is supported by an EPA review of the data, that
notes dosing-related nasal tissue histopathology in the F344 rat study
“extending, at least equivocally so, to the lowest dose of 100/50 ppm” ((May
27, 1999; MRID 44782301, p. 21). These
reviewers state that, “This
histopathology, including hyperplasia, would be considered pre-neoplastic and
supportive of a positive neoplastic response in terms of the rare nasal tissue
neoplastic findings observed” (p. 21, ibid).
and also express equal or greater concern regarding four rare oral cavity
neoplasms. These may be of greater concern because two of the lesions were
identified in the lowest dose group, 100/50 ppm, one in males and one in
females (p. 21). For neoplastic
findings, the reviewers find that the study is considered positive at high doses
based upon the finding of rare nasal tissue neoplasms, and extensive nasal
histopathology. The study is
considered positive at all doses attributable to rare neoplastic findings, two
of which occured at the 100/50 ppm dose level, one each in rats of each sex,
supported by evidence of a dose response for the same rare findings at 6000 and
12000 ppm in males. (p.22).
The Malathion Guideline 13-week subchronic inhalation study in the rat (MRID
43266601) yeilded evidence of nasal non-neoplastic histopathology similar to
that of this two-year feeding study, namely, degeneration and/or hyperplasia of
the olfactory epithelium. These
effects were seen after only 13 weeks and occured at all test concentrations.
(p. 22). For these reasons, NRDC
regards EPA’s decision to ignore oral and nasal tumors to be without merit.
Further, from a legal and environmental health perspective, even if the
scientific data were equivocal, or etiology could not be determined with
certainty, EPA should regulate on the side of precaution and protection.
The malathion docket contains several scientific articles,
in reputable, peer-reviewed journals, stating with confidence that malaoxon, the
first and main metabolite of malathion, induces DNA-damage and is genotoxic.
NRDC has serious concerns about EPA’s disregard for this information
and believes that the Agency has unjustifiably concluded that the information
should not be considered when evaluating the risks of malathion.
Comments by Dr. Needleman further support our concern (Needleman letter,
Sept. 20, 2000).
Malathion’s toxicity to insects and humans is triggered
when it is metabolized in the body to malaoxon. In fact, it is thought that the
insect’s more efficient metabolism of malathion to malaoxon that confers its
disproportionate acute neurological effects on that species instead of mammals.
However, also of key concern to the agency is the information it has
collected but ignored that documents the mutagenic potential of malaoxon.
These effects must be taken into account to properly consider the
mutagenic potential of the parent compound.
Malaoxon and leukemia
Ignoring the key results of a study involving the
carcinogenicity/chronic toxicity potential of malaoxon (MRID 43975201), EPA has
concluded that there is “no evidence of carcinogenicity in male or female
rats” (HHRA-RED, p. 14, 21). This
conclusion is contradicted by a separate supplemental analysis of the same data
by HED (MRID 44479301; in docket 24/OPP#00670).
This document concludes that leukemia was a statistically significant
positive response among male rats exposed to the highest two doses of malaoxon.
Comments by Dr. Dementi point out that leukemia is a late-onset disease,
and that its full expression in the higher dose groups was possibly compromised
by high mortality (June 8, 2000; 31/OPP#00670), further supporting concerns
about malaoxon triggered by these results.
Given the statistically significant increase in leukemia
in just this study, EPA’s statement that there is “no evidence” is a clear
misrepresentation of the data. Furthermore, an NCI study by Huff et al (1985)
found statistically significant increases in C-cell adenomas of the thyroid
gland in male rats exposed to malaoxon, and increases in adenomas and carcinomas
combined in males and females. This
NCI study concludes that there is “equivocal evidence of carcinogenicity”
for malaoxon in male and females, based on lesions of the thyroid.
Although EPA refers to this study as concluding that there is no evidence
of carcinogenicity for malathion, EPA disregards the positive findings regarding
Accounting for the Toxicity of All Metabolites and Stereoisomeric
Many pesticides, including organophosphate insecticides,
have toxicologically significant metabolites and stereoisomers. For example,
malaoxon — the bioactivated form of malathion — inhibits
acetylcholinesterase about 1,000–fold more strongly than does malathion.[i]
The impact of malaoxon and other metabolites on developing animals — where
even short-lived compounds could conceivably have irreversible effects on the
nervous system — is unclear, but heightens the need for prudence in carrying
out cumulative assessments. EPA
appears to have no requirement for chemical-specific pharmacokinetic studies in
developing animals that would aid in discerning the contribution of important
metabolites, such as malaoxon or dimethoxon, to children’s risk.
The Malathion Human Health Risk Assessment identifies
malaoxon as a metabolite. With
regard to residues in crop commodities, the Assessment (HHED-RED, p. 27) reports
that the oxon represents a small portion of total residues.
Groundwater monitoring data were available for the parent compound only,
and it was considered conservative to assume oxon residues at the same level as
parent (p. 32). However, parent and
oxon were combined to represent total residues in groundwater, suggesting that
the oxon was assumed at toxicity equivalent to the parent.
Chemical specific data for malathion were not submitted to the Agency to
estimate mixer/loader/applicator exposures (p. 35).
A transferable residue study on turf was submitted, but only parent
residues were measured (p. 39).
The Human Health Risk Assessment reports limited toxicity
data on malaoxon. This metabolite
was found to be negative for cancer, but a chronic NOAEL was not established for
cholinesterase inhibition (p. 14). Acute
toxicity data were not submitted, but the Assessment (p. 11) notes a literature
reference from 1966 [the Assessment did not include a bibliography, and the
Toxicology Chapter cited the same reference, but did not include that reference
in the bibliography; it is assumed that the date is not a misprint] reporting
the actue oral toxicity of malaoxon as 10 to 30 times that of the parent.
More recent references indicated much higher relative toxicity for
malaoxon (HHRA-RED, p. 11). Thus,
even if oxon residues are present at less than 1% of parent residues, the oxon
could dominate overall toxicity.
Chiral compounds are those which have two or more
stereoisomers, or enantiomers, identical in their constituent elements, but
which are mirror images of one another. Enantiomers
can vary greatly in their individual toxicity. The most potent malaoxon
stereoisomer may be 22,000 times more potent an inhibitor of some types of
cholinesterase than is malathion.[ii]
In terms of developmental toxicity, the importance of
stereoisomeric mixtures is evident from experience with thalidomide.
Dr. Chuck Thompson reports that after the teratogenic effects of
thalidomide were discovered, analysis showed that thalidomide was in fact a
stereoisomeric mixture with one stereoisomer conferring positive effects to
prevent morning sickness while the other stereoisomer possessed teratogenic
It has been suggested that at least seven of the thirty
seven organophosphates registered by EPA have chiral centers, and therefore the
potential for steroisomeric forms with vastly different toxicities, or chiral
degradates or contaminants.[iv]
These include malathion, naled (which has a chiral carbon atom),
cadusafos, (two chiral carbons, four enantiomers), fenamiphos, isofenphos and
profenofos (all of which have chiral phosphorus atoms).[vi]
EPA has stated that it does not know the relative ratios of the specific
enantiomers in the technical products of cadusafos, naled, fenamiphos,
isofenphos and profenofos, and presumably malathion – since the Human Health
Assessment (p. 8) does not report enantiomer ratios under physical/chemical
Chiral OPs therefore are sold as mixtures, with two or
more enantiomers of possibly varying toxicity, and EPA has no regulation or
optical rotation data to assure that this mixture remains identical from one
batch of the pesticide to another.[viii]
Naturally, the toxicity of the stereoisomeric mixture probably will vary
as the mixture itself varies—perhaps widely—from one pesticide lot to
another. EPA admits that it as yet
has no policy on how to treat chiral OPs. In
the interim, it simply assumes that the stereoisomeric mixture that was
registered is the one to which any person is exposed.
This assumption is both unscientific and lacking in
protectiveness. Until data are available that are specific to mixtures of
stereoisomers or other parent compound/metabolite mixtures for individual
pesticides, any cumulative risk assessment involving these chemicals (including
that for the organophosphates) will be incomplete. In this case, EPA should retain an additional 10X factor in
its risk assessments as mandated by FQPA for toxicity data gaps.
The EFED RED Chapter for Malathion (19/OPP#34223)
summarizes the major ecological issues of concern for malathion usage:
malathion is highly toxic to aquatic organisms, at levels
in current usage
malathion is potentially hazardous to reproductive success
of certain species of birds and mammals, at currently registered use rates.
malathion is highly toxic to beneficial insects, at
current use rates.
malathion has a high potential to drift off target, during
malathion is routinely detected in tributaries and ponds,
and has been the cause of fish kills in slow-flow-rate ponds and streams
malathion converts to the active, toxic, metabolite,
malaoxon during the processing of surface water to drinking water, and in the
presence of certain chemicals used in swimming pools
sublethal effects of malathion on birds and reptiles may
include altered behavior, disorientation, and loss of motor control.
Presumably the above concerns, while focused on wildlife,
would also represent increased risks for humans who, though not lethally
affected, are susceptible to disturbances in neural processing and function.
Any disturbances in reproductive abilities in mammals would also
presumably be of concern for humans. Effects
such as disorientation and loss of motor coordination, while affecting a small
mammal or bird profoundly, would presumably have for subtle, but critical
effects on humans.
Ecological data gaps
The EFED RED Chapter for Malathion summarizes the major
data gaps for ecological issues of concern for malathion usage:
environmental fate for malathion
aerobic aquatic metabolism
environmental fate for malaoxon
EFED acknowledges that malaoxon is commonly believed to be
the neurotoxic agent of malathion, and states that toxicity data show it to have
higher acute toxicity than malathion. (p. 5). Conversion levels as high as 10.7% have been reported by
CalEPA (1993), and HED has indicated that malaoxon is to be included in the
tolerance expression for malathion. (EFED, p. 5).
Thus, EFED states that malaxon data represents a critical gap in the data
base. Gaps in the data base include
malaoxon degradation, metabolism, and mobility (EFED, p. 5-6).
malathion data base is several decades old, and needs to
there are no submitted toxicity data on the mixture of
malathion and methoxychlor
there are no studies on chronic effect levels of malathion
on estuarine fish or invertebrates
there is no data on full life-cycle testing in fish
there is insufficient information on the toxic effects,
including developmental effects, of malathion in beneficial insects and
malathion has been shown to affect the ability of mice to
run a maze, the ability of fish to swim against a current, and the nesting
success of grouse.
malathion may lead to chronic reproductive and sublethally
adverse effects to sensitive species
The above data gaps represent a serious concern in
evaluating Public Health risk. This
gap in the data more than justifies use of the 10X FQPA safety factor.
Gaps in Exposure Data
Although good, reliable data currently exist on dietary
exposure to malathion and other organophosphates registered for use on
food—and on this basis alone current exposures are often found to exceed the
acute or chronic reference dose—there are critical data gaps in terms of
non–food exposures. These gaps in
exposure data provide compelling additional justification for retaining the FQPA
10X safety factor for the assessed OPs. However, EPA has failed to retain the
FQPA 10X uncertainty factor on the basis of gaps in exposure data for any
pesticide, including malathion.
Typically, these non-food exposure data gaps include the
lack of actual monitoring data for drinking water. While modeling drinking water exposure is useful for
estimating risk, it cannot be considered “reliable data” for the purposes of
deciding whether EPA retains the additional child-protective uncertainty factor
under section 408 of FFDCA. In the
case of malathion, the Human Health Risk Assessment reported very limited
monitoring data from groundwater, along with modeling data for surface water
sources (p. 30). Monitoring data
for malaoxon, the far more toxic degradate/metabolite, was even more sparse.
Exposure data gaps also include a lack of data on
residential exposures either due to registered uses in or around homes or
schools, and due to “take home” exposures to pesticides not registered for
residential use but that may be tracked home on the contaminated hands, shoes or
clothing of people exposed to pesticides at work. Even though EPA’s own EFED
found that malathion has a high potential to drift off target (19/OPP#34223).
EPA also typically lacks “reliable data” on exposures due to air
drift. These latter exposures are of concern to people, especially children,
living, playing or attending school beside or near to treated fields,
particularly when the pesticide in question is applied by air.
The lack of such reliable data on exposure compels EPA to retain the FQPA
10X uncertainty factor.
BURIED RISK ASSESSMENT ASSUMPTIONS
Many preliminary OP assessments contain buried assumptions
that receive little or no recognition in the risk characterization, despite
their less than health protective impact on final risk estimates.
These assumptions, in other words, will tend towards a lesser, rather
than a greater, certainty of no harm to infants and children.
EPA should acknowledge as much. For
example, EPA continues to use many mean or median values for parameters critical
to estimating children’s residential exposures.
Two examples are given below:
“toddlers”, ages 1 year to 6 years, are assumed to weigh 15 kg
or approximately 33 pounds. This
ignores enormous normal variation within this age group, as well as same-age
variation. The Malathion assessment
of child exposure from turf residues was based on the assumption of all children
under age six weighing 15 kg (p. 49).
generally assumes a toddler exposed to a surface contaminated with pesticides (a
counter, or a treated pet) puts his or her hand in the mouth just 1.56 times per
hour. The Malathion assessment represents an improvement over
previous practice with EPA assuming that children have hand-to-mouth behavior of
20 events per hour over two hours (p. 49), rather than that of 1.56 events per
hour. However, this assumption
still is based on a mean value. Researchers at Rutgers University, observing a
few dozen children, have found mean values of 9.5 hand–to–mouth
events per hour.
Mean values of nearly 26 behavior events
per hour have been observed for some children, while high-end individuals
may demonstrate up to 70 events per hour. Risk estimates based on even this mean
value of 20 will still not protect high-end children whose hand-to-mouth
behavior varies from hour to hour and whose acute exposures may go much higher
as hand-to-mouth events range up to 70 events per hour or more.
Since the mandate for a reasonable certainty means that
EPA must set tolerances so as to protect the exceptional child, in terms of
pesticide exposures, and not the average child, use of these central tendency
estimates are inappropriate. Where use of these assumptions will tend to
understate true exposure and risk for particular subpopulations, it should be so
noted in the risk assessment. In
order to better protect the most vulnerable toddlers, we urge EPA to use upper
bound estimates for these parameters.
Preliminary risk assessments for several organophosphates
suggest that any agricultural use may present unacceptable risks to workers, and
perhaps to their families and children. These
chemicals may not be found "safe" under FFDCA section 408, and cause
"unreasonable adverse effects on the environment" under FIFRA.
Therefore EPA should issue an NOIC and proposal to revoke their
In the case of malathion, the Human Health Risk Assessment
identified 16 major exposure scenarios for applicators/mixers/loaders.
Five major scenarios were found to have acceptable exposures under
baseline conditions. With personal
protective equipment or engineering controls, two scenarios were still
determined to give unacceptable exposures (ARIs of 0.93 and 0.94).
For four scenarios, no appropriate data were available to determine risks
(p. 39). As with previous OP
assessments, however, EPA ignores the realities of the agricultural work
environment for malathion. The
margins of exposure (MOE) for agricultural tasks using malathion are calculated
based on the assumption that closed mixing and loading systems, enclosed
cabs/trucks, and enhanced personal protective equipment (PPE) would be available
to workers handling malathion. When evaluating the true risk to these handlers,
however the EPA must remember that in many instances PPE is not provided (and engineering controls will not be available); when
PPE is provided, it does not always fit properly; and often, PPE is too
uncomfortable to wear. Thus, in
real terms, the risk to farmworkers (as well as their families) probably will
far exceed the risks demonstrated by the EPA’s MOE calculations.
With regard to postapplication exposures for farmworkers,
reentry intervals (REIs) leading to acceptable exposures were estimated to range
from 1 to 6 days, compared to current REIs of 12 hours (p. 44).
Moreover, a recent study monitoring malathion bait spray residues found
that malaoxon formed on plant surfaces at levels about one tenth those of the
parent; yet these data were designated as insufficient to assess postapplication
exposure to malaoxon residues (p. 41).
It should be clear that setting conditions that adequately
protect workers, such as reducing application rates, increasing reentry
intervals, or halting uses on crops where adequate reentry levels cannot be
established, may have the additional effect of reducing pesticide residues on
food commodities. Moreover,
adequately protecting workers should reduce the levels of “take-home”
residues that can expose farmworker families, a particular population of concern
as described in following sections. Thus,
measures to adequately protect farmworkers can have additional favorable effects
in reducing cumulative risks from OP pesticides.
CUMULATIVE RISK ASSESSMENT
The malathion preliminary risk assessment covers this
single chemical only. The Human
Health Risk Assessment (p. 62) notes only that EPA is developing draft
methodology to conduct a cumulative assessment for organophosphates.
Most of EPA individual
OP risk assessments thus far have provided cause for human health concerns.
However, the organophosphates are also known to demonstrate a common
mechanism of human neurotoxicity through inhibition of the enzyme
individual assessments only lend fuel to the urgency for EPA to proceed with
cumulative risk assessment of the OPs as mandated by the Food Quality Protection
Act. Cumulative assessment, relative to individual chemical assessment, would be
expected to demonstrate much higher risks.
EPA must therefore aggressively pursue risk management not only for
individual chemicals, but for organophosphates as a class.
The Agency will not be meeting its public health responsibility, nor the
FQPA mandate, if it continues to refine risk assessments and pursues mitigation
only for individual chemicals.
These issues aside, EPA could improve the risk
characterization for individual OPs by including a discussion of the impact on
the final risk estimate of not including a cumulative assessment for two or more
OPs. In addition, it would be
helpful for the public and for EPA risk managers if Agency scientists were to
incorporate into each individual risk assessment a table summarizing the risks
for each of the 25+ OPs for which there has been a preliminary assessment thus
far. Essentially, this table would
provide a running total of the cumulative risk from OPs to date.
EPA could similarly use a table format to make clear to the public how
effectively Agency regulatory actions have reduced cumulative OP risks.
Risks to Workers and Workers’ Families
FQPA requires that EPA consider cumulative effects of
residues with a common mechanism of toxicity. FQPA § 408(b)(2)(D)(v).
There is no reason to believe that farmworkers are any less susceptible
to cumulative effects than the general population, and much reason to believe
that they are more highly exposed. Even
if EPA argues that it does not have to perform cumulative risk assessments for
farmworkers under FQPA, EPA's own rules have long required that "pesticide
chemicals that cause related pharmacological effects will be regarded, in the
absence of evidence to the contrary, as having an additive deleterious
action" and specifically includes pesticides that inhibit the
cholinesterase enzyme. 40 C.F.R. Part 180.3(a).
In any case, EPA must consider cumulative exposures to the children of
those handling pesticides resulting from take–home exposures on clothing,
skin, and hair, and equipment stored in the house.
EPA’s lack of a cumulative OP risk assessment is
compounded by its lack of urgency in taking even relatively simple
administrative measures to bound risks from malathion.
The Assessment (p. 24) for example, reports a laundry list of uses not
supported for reregistration:
All pet uses
All direct uses on livestock
All indoor uses, except stored commodities and storage
All greenhouse uses
All open-forest land uses
All seed treatments
All pressurized can formulations
All formulations for uses on:
Treated raisin trays
The Assessment notes that
these uses have been specifically excluded from the analysis for malathion.
Nevertheless, all these uses remain registered, and EPA may have little
idea of the overall exposure consequences.
The Agency’s assessment of malathion aggregate risk remains invalid
while these uses remain in effect. EPA
should cancel these unsupported uses, remove them from labels, and revoke
The Assessment also notes in its Executive Summary (p. 1) that only
risks from Section 3 registrations are evaluated in this document.
A separate risk assessment was recently conducted for malathion use for
medfly control under Section 18 registrations for California and Florida.
Details were not provided on the Section 18 assessment but this
revelation raises procedural concerns on several levels.
First, this seems a strange way to conduct aggregate risk assessment.
As long as malathion tolerances are in effect, aggregate assessment
should mean an evaluation of all pathways, not evaluation bifurcated by
registration status. Second, it is
abundantly clear that malathion and other OPs, pose unacceptable risks as
individual chemicals. EPA needs to
develop a comprehensive OP risk reduction strategy.
That will not be accomplished if EPA allows additional OP uses through
registrations via Section 18, Section 24(c), or new Section 3 uses.
Third, although there may be significant economic pressures for medfly
control, the granting of a Section 18 may violate the law.
If a tolerance or an exemption from tolerance is established, even a
time-limited tolerance requires a determination of safety, which EPA cannot
credibly issue, either for malathion aggregate risks, or for any OP chemical on
the basis of cumulative risks. EPA
should explain both on a policy basis and on a legal basis why it has allowed
Section 18 loopholes for malathion.
Additional concerns are raised by the Assessment’s description of
outstanding reregistration data requirements, which are conveniently labeled as
“confirmatory” (p. 64). These
include crop requirements that should have been satisfied long ago, such as
field trials for celery and apples, wheat processing data, and field rotational
crop studies. Moreover, one
particular category suggests a case study in regulatory lag: Requirements imposed by the Malathion Reregistration Standard
[issued thirteen years ago, in 2/88] remain outstanding for data on nature and
magnitude of residues in drinking and irrigation water from aquatic uses.
Thus, registrants have failed to meet these requirements for more than a
decade. EPA simply should not
tolerate additional delay, and should cancel the applicable registrations on the
basis of flagrant negligence of registrants in meeting data requirements.
If EPA will not enforce its own regulatory data requirements, it is even
less likely to stand up to chemical companies and make more difficult decisions
to reduce real risks from OPs and other pesticides.
REASONABLE CERTAINTY OF NO HARM
EPA's risk assessment for malathion fails to meet
the FQPA health–based standard that there be a "reasonable
certainty" of no harm to infants and children. This risk assessment is
inadequate and less than transparent in its description or characterization of
risk. Ultimately, this inadequate
characterization will make it more difficult for EPA risk managers to make a
tolerance determination with "reasonable certainty." Among the risks requiring full characterization — to
provide a reasonable certainty of no harm to children and others living in or
adjacent to areas where pesticides are applied — are risks from
“take–home” exposures as well as from spray drift.
Take-home exposures include home exposures of pregnant women and children
to malathion tracked home on the clothes, shoes, and skin of workers.
Air drift exposures include the exposure to people on the ground from
aerial spraying, as well as residential exposures arising from chemicals with
terrestrial field applications that subsequently disperse on the wind to
adjacent homes and lawns. Other EPA approaches such as calculating acceptable exposures
using other than a No-Observed-Adverse-Effect-Level (NOAEL) appear both less
than health protective and contrary to the intent of Congress.
Finally, there can be no scientific basis for EPA conducting a risk
assessment for malathion without also considering all the risks stemming from
exposure to malaoxon, and other metabolites.
Jennifer Sass, Ph.D.
Natural Resources Defence Council
[i] Rodriguez OP, Muth GW, Merkman CE, Kim K, Thompson CM, “Inhibition of Various Cholinesterases with the Enantiomers of Malaoxon,” Bull. Environ. Contam. Toxicol. 58:171-176 (1997).
[iii] Personal communication with Chuck Thompson, Ph.D., Chemistry Department, University of Montana.
[iv] US EPA Memorandum, Response to Public Comments on the Preliminary Risk Assessment for the Organophosphate Sulfotepp, June 30, 1999, http://www.epa.gov/opssrrd1/op/sulfotepp/response.pdf.
[v] See Berkman CE, Thompson CM, “Synthesis of Chiral Malathion and Isomalathion,” Tetrahedron Lett. 33:3313-3320 (1992); Berkman CE, Ryu S, Jackson JA, Quinn DA, Larsen A, Thompson CM, “Stereochemical Aspects of Organophosphate Toxicity,” In Rev. Pestic. Toxicol. (Roe and Kuhr, Eds.), Toxicology Communications Inc., 2:131-146 (1993); and Berkman CE, Quinn DA, Thompson CM, “Interaction of AChE with the Enantiomers of Isomalathion and Malaoxon,” Chem. Res. Toxicol., 6:724-730 (1993).
[vi] US EPA Memorandum, Response to Public Comments on the Preliminary Risk Assessment for the Organophosphate Sulfotepp, June 30, 1999, http://www.epa.gov/opssrrd1/op/sulfotepp/response.pdf.
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