NRDC comments

OPP Docket
Rm. 119, CM #2
1921 Jefferson Davis Highway
Arlington, Virginia
Docket Number: OPP-34223

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 comments.

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 three.

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.

· 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.

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 discussed here.

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 malathion.

· 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 EFED

· No data on malaoxon fate, degradation, metabolism, and mobility; data gap cited in EFED

· 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

· 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

C. EPA Has Underestimated Exposure risks; Failed to Consider Aggregate Risks for Malathion

In 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.

EPA’s 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).

The legal analysis submitted by Farmworker Justice Fund to the Pesticides Docket for the chlorpyrifos risk assessment, has equal applicability to Malathion:

“In 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

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 99.9^th 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 Nebraska, Lincoln.)

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 the home.

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.

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 assessment data.

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.

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).

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.

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.

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 here.

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.

D. 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 malathion.

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 this compound.

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 Malathion.

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 42945-42947). Individual 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 organophosphate insecticides.

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.

Both 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.

NOELs 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.

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 99.9^th 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 95^th 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.

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 well.

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 determination.

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 with no 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 Public Health.

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 these tumors.

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 concerns.

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 warrented.

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.

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 malaoxon.

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 properties.[iii]

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] [v] 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 properties.[vii]

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 potentially hazardous to reproductive success of certain species of birds and mammals, at currently registered use rates.

· 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.

The EFED RED Chapter for Malathion summarizes the major data gaps for ecological issues of concern for malathion usage:

· 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).

· 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 insufficient information on the toxic effects, including developmental effects, of malathion in beneficial insects and amphibians.

· 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.

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.

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:

· All “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).

· EPA 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 tolerances.

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.

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 cholinesterase. Therefore, 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.

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:

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 applicable tolerances.

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.

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.
Senior Scientist
Natural Resources Defence Council
Washington, DC

[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).

[ii] Ibid.

[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.

[vii] Ibid.

[viii] Ibid.