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Charge to the Expert Panel

The Agency for Toxic Substances and Disease Registry (ATSDR) convened an expert panel workshop on April 24 and 25, 1997, in Atlanta, Georgia, to discuss issues related to illegal spraying of the pesticide methyl parathion (MP) in residences. The purpose of the expert panel was to assist ATSDR, the U.S. Environmental Protection Agency (EPA), and state and local health departments in addressing key issues of science, public health practice, and risk management related to this indoor use of methyl parathion. The panel was asked to address a set of key issues raised by the governmental interagency Methyl Parathion Health Sciences Steering Committee (hereafter, the steering committee).

The expert panel decided to address these issues in two separate work groups: Risk Identification/Management and Public Health Practice. The Public Health Practice Work Group further subdivided their tasks into Health Education/Risk Communication and Clinical Practice. The Risk Identification/Management Work Group was chaired by Daniel Hryhorczuk, MD, MPH, and comprised Janice Chambers, PhD, Jim Riviere, DVM, PhD, Stanley Shuman, MD, PhD, and Sheldon Wagner, MD. The Public Health Practice Work Group was chaired by Caron Chess, MS. Members of the Health Education/Risk Communication subgroup were Ms. Chess and Luz Claudio, PhD. Members of the Clinical Practice subgroup were Mike O'Malley, MD, MPH, and Victor Roth, MD, MPH. This report includes the advice and recommendations of the individual work groups as well as advice and recommendations on overarching issues between the work groups that were addressed by the expert panel in plenary session. The panel also identified critical data gaps and knowledge needs that must be addressed to develop science-based risk management decisions.

The opinions and recommendations put forth by the panel are based on a time-limited review of materials and data that were presented to the panel by organizers and observers, as well as on our personal expertise and experience. These opinions and recommendations are not based on a critical review of all available scientific literature on these topics or a thorough review of all available field data collected by these agencies. For those reasons, we believe that the opinions and recommendations in this report should be continually re-examined and action plans updated as new or previously unreviewed data become available. Also, the panel was asked to focus specifically on MP and did not address the issue of combined exposures to multiple pesticides or other environmental toxins. The panel acknowledges that concurrent exposures to other agents may occur; such exposures should be considered in site-specific risk management.

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Issue: Environmental fate and biomonitoring

What are the appropriate environmental sampling methodologies to characterize the extent of contamination in indoor settings?

The panel was informed that applications of methyl parathion in residences were made by numerous methods such as broadcast and spot application. The frequency and amount applied in these cases was not systematic and varied widely among residences. It is the opinion of the Risk Identification/Management Work Group that broadcast applications have the greatest potential for adverse human health effects.

The principal route of exposure route is most likely dermal, especially in infants and young children. In the latter, there may also be smaller amounts of exposure through the respiratory route and an undetermined amount by the oral route.

The relative amounts of environmental degradation products of MP in these settings are not clearly known and may be important because of formation of small amounts of para-nitrophenol (PNP). If MP is resulting in significant PNP production, then a mixture of MP/PNP may be exposing individuals. Dr. Riviere's laboratory has shown that when PNP and ethyl parathion are co-dosed, two events may happen: (1) PNP enhances ethyl parathion absorption, and (2) PNP is rapidly absorbed and shows up in urine as PNP. No similar studies have been done with MP. The importance of this data is that "old" MP (i.e., MP that has been in houses for prolonged periods) may have PNP, which would be reflected in increased PNP in urine test results. Such results do not reflect MP exposure and would indicate minimal toxicological risk.

The effects of PNP on MP have not been studied. Similarly, Dr. Riviere's group has shown that exposure of parathion simultaneously with other pesticides may modulate their absorption, often blocking it (e.g., as fenvalerate does). Therefore, these effects with MP may be important and should be investigated in a relevant animal model for human absorption such as the pig or monkey.

Recommendations

1. The topic of environmental degradation products of methyl parathion in these settings is a critical data gap. We recommend that the agencies monitor surfaces for MP and PNP in representative samples of homes to determine the need for systematic sampling for these degradation products in all homes.

2. The work group agrees with the steering committee that baseboard wipe sampling is acceptable as a general index of household contamination because it appears that MP was applied to these surfaces in all cases. Baseboard sampling should be mandatory in all suspect residences. A systematic sampling protocol for baseboards that specifies which locations, as a minimum, are to be sampled appears reasonable. The work group cautions that, although baseboard sampling is a reasonable screen for the presence of contamination, these samples may not accurately reflect the true potential and degree of exposure and must be supplemented with additional sampling as described below.

3. The work group concurs with the steering committee's assessment of the need for additional mandatory sampling, the type and location of which is determined at the time of on-site inspection. The work group supports the use of a household environmental exposure questionnaire to assist in determining the most appropriate locations for additional sampling. These additional samples should include surfaces with dislodgeable residues where contamination is suspected and exposure is most likely.

4. Air samples for MP should be performed in rooms with known or suspected contamination of heating systems. Air samples should be taken with the heating systems on and at sampling heights that reflect exposure to infants and toddlers.

5. The work group recognizes that there may be important regional differences in environmental factors (such as climate and type of residences) that affect household MP exposure. If the discretionary sampling identifies important regional differences, regional agencies should have the flexibility to adjust their environmental sampling protocols to minimize misclassification of contaminated homes.

What are the health endpoints of concern associated with chronic exposure to methyl parathion in indoor settings?

Methyl parathion is an organophosphorous (OP) insecticide of the phosphorothioate group. According to conventional wisdom, OP insecticides or their active metabolites elicit toxicity by inhibition of nervous system acetylcholinesterase (AChE). Inhibition of AChE leads to accumulation of the neurotransmitter acetylcholine (ACh), leading to hyperactivity in cholinergic pathways present in the central nervous system and peripheral nervous system, and both automatic and somatic pathways within the peripheral nervous system. Thus the resultant hypercholinergic activity leads to a variety of signs and symptoms, some of which (the respiratory) can be life-threatening if poisoning is from a sufficiently high level.

MP requires metabolic activation to methyl paraoxon (MPO) to yield appreciable anticholinesterase activity; MPO could phosphorylate serine esterases other than AChE or serine proteases. Inhibition of these other enzymes, if they are noncritical enzymes, could be protective (they could have a scavenger function) or, conversely, could yield toxicities unrelated to AChE inhibition.

It is the opinion of the work group that peripheral neuropathy, which has been seen with other OPs, is not a consequence of MP exposure. Also, evidence is not great for other target organ toxicities at doses lower than those causing neurotoxicity.

Blood cholinesterase (ChE) inhibition is a biomarker of exposure. However, agreement does not exist regarding how much blood ChE inhibition correlates with nervous system AChE inhibition or how much AChE depression is required for neurobehavioral toxicity. Several detoxication enzymes exist that can potentially degrade MP or MPO. If these detoxication reactions occur efficiently enough, then MPO will not have the opportunity to inhibit ChE, either in the brain or the blood. It is expected that effective detoxication will occur at low-dose levels. Thus, if analytical chemistry techniques are sensitive enough, urinary PNP will reflect lower exposure levels than red blood cell (RBC) ChE inhibition will. The body is well adapted to respond to change and stressors (chemical or otherwise). Maintenance of homeostasis would be expected whenever any AChE inhibition leads to hypercholinergic activity through down-regulation of neurochemical functions. The magnitude of such homeostatic compensation at different ages and in different physiologic states is not known. For this reason, biomarkers of exposure may not be entirely predictive of biomarkers of effect.

Neurobehavioral effects have been noted experimentally following MP exposure in experimental animals; it is logical that this would be one of the major, if not the major, potential toxicity against which public health policy needs to protect.

Infants and children have immature low levels of xenobiotic metabolizing enzymes and lower renal clearance rates. This lower level of protection (compared to that of adults) makes them more sensitive to the effects of MP because they achieve higher internal doses. Because both AChE and acetylcholine appear to be morphogens within the developing nervous system, perturbing the structure or function of AChE and elevation of ACh levels could have deleterious effects on the development of normal connections in the maturing nervous system.

Much of the above is logical extrapolation to humans from data generated in experimental animals. One critical data gap is the sensitivity of human blood, liver, and brain esterases to inhibition by MPO and the likelihood of MPO degradation by plasma and liver A-esterases; the biochemical protection available to humans is not known and, therefore, predictions of the disposition and internal dose of MPO cannot be made. A second critical data gap is the development of these same enzymes in humans; the vulnerability of the infant or child cannot be predicted compared with that of the adult.

Exposure to MP can result in a range of signs and symptoms that are dose- and host-dependent. These symptoms can range from subtle neurobehavioral disturbances to nonspecific symptoms such as nausea; diarrhea; dizziness; confusion; blurred vision; excessive sweating, tearing, and drooling; weakness or muscle twitching; to acute cholinergic crisis with severe manifestations of the above symptoms. Direct experience in locations where indoor spraying has occurred indicates that most household members are likely to be asymptomatic or have low-grade symptoms.

What populations are susceptible to adverse health effects as a result of exposure to methyl parathion?

The work group agrees with the steering committee that there are high-risk groups in the general population who are likely to be more susceptible to developing toxicity from MP exposure. These high-risk groups require greater levels of protection, which would include more intensive biomonitoring for exposure and lower thresholds for public health interventions. The work group also agrees with the steering committee that age is an important risk factor for MP toxicity. In addition, the work group has identified the following high-risk groups not considered by the steering committee:

• The fetus (and by extension, pregnant women). The developing nervous system is a potential target organ for MP neurotoxicity (see discussion, pp. 4-5). The degree of susceptibility and the degree of protectiveness afforded by maternal clearance and defense mechanisms compared with those of infants are unknown.

• Infants and children. Immaturity causes low levels of xenobiotic metabolizing enzymes and decreased renal clearance, making infants and children more susceptible than are adults to MP toxicity. In addition, the brain continues to develop after birth and continues to form neural connections through adolescence (age 16). Younger children are likely to be more susceptible than older children, but the magnitude of risk at specific age groups is unknown.

• People who have impaired hepatic or renal clearance (e.g., elderly with poor liver or kidney function or people with liver or kidney diseases that impair clearance).

• People using medication for chronic diseases, or other purposes, whose pharmacokinetics may be affected by MP exposure (e.g., people with kidney or liver transplant).

• Mentally disabled people who may not be able to adequately comprehend and evaluate risk or follow public health interventions based primarily on health education.

• People who have other sources of exposure to OPs (e.g., occupationally exposed people).

Recommendations

1. The work group agrees with the steering committee proposal to have risk-group-specific urinary PNP relocation action levels.

2. Infants (children less than 12 months of age) are clearly a very high risk group and require the lowest urinary PNP relocation action levels.

3. It is the opinion of the work group that the fetus may be as susceptible to MP neurotoxicity as infants, or more so. The degree of protection afforded by the mother is unknown. The steering committee should weigh these considerations and review any available scientific evidence that addresses fetal susceptibility and maternal protection. If the data suggest that maternal protection does not afford ample protection to the fetus, or if there are insufficient data to resolve this issue, then putting pregnant women into the highest risk group, along with infants, would improve the public health protectiveness of the relocation criteria.

4. Because the central nervous system continues to develop and mature through adolescence, the age band for children should be expanded through adolescence (age 16). The steering committee's proposed cutoff of 5 to 6 years was based, in part, on age-specific differences in opportunities for exposure. Because urinary PNP is a biomarker of exposure, an elevated urinary PNP indicates exposure, regardless of the underlying behaviors leading to that exposure.

5. Although separate action levels based on urinary PNP levels for pregnant women and children are reasonable, individual risks among members of other high-risk groups are likely to be highly variable and situation-specific. We recommend that local public health officials have the flexibility to exercise judgement in evaluating biomonitoring results from members of other high-risk groups and be allowed to recommend public health interventions accordingly.

Given the specific characteristics of indoor exposure to MP, how do we monitor a population to adequately evaluate exposure?

There is a preponderance of evidence that monitoring urinary metabolites of OPs is a good index of low-level exposure. Studies in humans have shown that urinary measurement of PNP is a good index of MP exposure. The Morgan study of human volunteers demonstrated substantial excretion of this metabolite within 24 hours after oral exposure. Many limitations exist in the Morgan study including oral vs dermal route, small sample size, incomplete measurements of PNP and dialkyl phosphates, and no mass balance. In addition, the elimination kinetics measured in this intermittent oral dosing study may not accurately reflect steady state conditions or the intermittent dermal dosing likely to be occurring in the field. Sustained dermal absorption should produce more consistent urine PNP data. It is also possible that absorption is occurring from multiple routes. For these reasons, longer urine collections are required.

Although a 2-hour urine sample would be preferable, field experience has demonstrated that this procedure is not practical in this situation. In previous biomonitoring conducted by EPA and ATSDR, random samples have been extrapolated to 24-hour urine volume. A preferred method would be creatinine adjustment by age, sex, and weight. It is critical to learn what the variation in urinary PNP excretion will be under the proposed sampling protocols to evaluate the protocol's ability to reasonably estimate MP dosing under various exposure scenarios. Until these data become available, the work group cannot assess how closely spot collections of urinary PNP estimate actual MP exposure.

In addition to urine sampling, an individual exposure questionnaire should be administered before urinary PNP sample collection to ensure that the sample has a reasonable likelihood of assessing exposure.

Recommendations

1. The work group has identified the variability in spot samples of urinary PNP (both day-to-day and diurnal) as a critical data gap. Until this variability is measured, the ability of the proposed biomonitoring protocol to estimate MP dosing under various exposure conditions is undetermined. The pilot data from Memphis indicates great variability in A.M. and P.M. urine concentrations. It must be recognized that there are different uses of urine PNP data. Spot samplings have been primarily used to detect contamination. However, the lack of correlation with absorption because of different exposure patterns. This issue needs to be addressed in a proposed 7-day study collecting A.M. and P.M. samples to determine variability. People with different exposure scenarios should be selected and the variability specifically assessed. It is also possible that the peak samples may prove useful to establish better cutoff points by offering better correlation with dose and any long-term subchronic effects.

   The "ideal" collection would be a pooled 24-hour sample: a complete collection of urine voided over a 24-hour period with testing of the PNP concentrations excreted during individual time intervals, and assessment of the PNP excretion over the 24 hours. The work group strongly recommends that the steering committee initiate a minimum 7-day study of urinary PNP biomonitoring (A.M. and P.M. minimal; 24-hour ideal) concurrent with environmental assessment to examine this issue. This pilot study will help the steering committee determine the minimal number of samples and sampling frequency required to assess overexposures using urinary PNP biomonitoring. The timing of the spot urinary PNPs should be based on the individual exposure questionnaire. Adjusting the spot urine test results for creatinine may reduce variability as described below. The usefulness of this adjustment can also be assessed in the 7-day study.

2. The work group suggests that urine concentrations of PNP be corrected by urine creatinine concentrations to better reflect true MP clearance. The optimal approach would be to normalize creatinine to sex and body surface area as is done by clinical pharmacologists/nephrologists when dosing patients who have wide ranges of renal functions. In the case of MP, the justification is to correct for individual differences in urine concentration due to either homeostasis or renal disease where low PNP concentrations may be due to age or dilute urine rather than to low exposure to MP. The steady state production and excretion of creatinine into the urine may help normalize these variables.

What is the appropriate length of time to conduct biomonitoring to assess continued exposure? For susceptible populations, should biomonitoring occur beyond the time period for nonsusceptible populations?

The work group reiterates that both the frequency of biomonitoring and duration of biomonitoring should be based on field data rather than simply theoretic considerations. The environmental sampling data collected to date, when plotted against time since application, appear to show a long environmental half-life (227 days). Available data should be examined to see if similar temporal associations exist using urinary PNP as a measure of exposure, and how declines in urinary PNP relate to natural or clean-up related declines in indoor MP contamination. The current proposal to monitor at least 1 year appears to be a reasonable minimum. Longer biomonitoring may be required if accumulating data indicate the potential for the biomonitoring schedule to miss overexposure situations even after 1 year of followup. The estimates of variability that will be provided by the 7-day study will also help to address this issue .

Another important scheduling issue regarding the biomonitoring program is the frequency of sampling. If the 7-day study indicates high variability among spot urinary PNP samples, then the frequency of sampling may need to be increased. If more frequent urinary PNP samples need to be taken, it is preferable to weight these earlier in the course of biomonitoring to minimize continuing exposures due to misclassification errors. Finally, the work group concurs with the concept that high-risk populations may require more intensive biomonitoring (longer and perhaps more frequent); again, these decisions should be based on the considerable amount of data that is being accumulated.

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Issue: Correlation of environmental and biological data

Do the correlations provided in this analysis demonstrate associations strong enough to be used for risk management decisions? If so, how? If not, what recommendations would the panel make to enhance predictability from the two sets of data?

At this point, no. In this analysis ATSDR attempted to determine the extent of the relationship between an individual's urinary PNP level and age and environmental MP levels. Environmental data included wipe sampling data of MP for 406 households; urinary PNP data included levels for 858 participants. Environmental data were reduced to three summary variables: "kitchen composite"; arithmetic average of all samples from a household; and sampled values around the kitchen sink. Analysis consisted of linear and ordinal logistic regression of log-transformed data. Although the analyses demonstrate a general relationship between extent of environmental contamination and urinary PNP, the ability of the models to predict urinary PNP based on environmental MP contamination was poor.

The lack of a stronger association between measures of environmental contamination and urinary PNP as a biomarker of exposure is not surprising. Environmental sampling was designed to identify worst-case scenarios and may not be representative of surfaces that actually accounted for people's exposures. A major determinant of exposure is human behavior (i.e., behavioral factors account for contact with contaminated surfaces), which is not addressed in the analysis. Furthermore, sources of error in using urinary PNP as a biomarker of exposure have already been addressed. The reduction of measurement error through the use of exposure questionnaires to select appropriate environmental samples and timing of urinary PNP bioassays, use of creatinine-adjusted PNPs, use of environmental samples that more closely estimate actual exposures, and measures of high-risk behaviors temporally related to the times of collection should improve the predictive capability of future regression models.

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Issue: Appropriateness of Relocation Criteria

Public health and regulatory agencies typically recommend that continuous human exposures to toxic substances not exceed a dose that is tenfold to a hundredfold lower than a dose that causes no observable adverse effects (NOAEL) in study populations. EPA has formalized this process by including, when available, chemical-specific values, reference doses (RfD), in its toxicity database used by regulatory programs. A subchronic RfD for methyl parathion has been established by EPA. Although RfDs are generally considered to be screening levels and are not regulatory standards, they are often used to establish environmental cleanup levels.

The proposed urine levels based on other health criteria are about thirtyfold higher than EPA's subchronic reference dose (RfD), threefold higher than some animal no-observed adverse effect levels (NOAELs), and about threefold lower than the lowest observed adverse effect levels (LOAELs) found in recent subchronic animal studies. In consideration of the chronic toxicity and degradation of methyl parathion and the likely exposure time and pattern for affected persons, are the proposed urine PNP criteria sufficiently protective for all persons? If not, what criteria would the panel recommend?

The proposed relocation criteria rely on (1) environmental sampling to classify homes as contaminated or noncontaminated; (2) biomonitoring of occupants of contaminated homes for urinary PNP as a biomarker of MP exposure; and (3) relocation of an entire household if the urinary PNP of any single member exceeds the risk-group-specific urinary PNP action level. The work group concurs with the steering committee that urinary PNP is an appropriate biomarker of low-level MP exposure. The work group also concurs with the steering committee that reference doses (RfDs) are screening values and that a weight-of-evidence approach is reasonable as applied to specific exposure situations. The work group concurs with the approach to base relocation criteria, as a minimum, on risk-group-specific urinary PNP biomonitoring.

The work group recognizes that where to set the urinary PNP action levels is a risk management decision faced by the involved governmental agencies. However, we have identified critical gaps that preclude our ability to endorse or refute specific action levels on a scientifically substantiated basis. We strongly feel that resources should be devoted to generating the data necessary to fill these gaps as quickly as possible. It is critical to conduct a dermal absorption study correlating MP dermal dose with urine PNP excretion pattern. Although such a dermal absorption study in human volunteers would be ideal, valuable data can also be obtained from the use of relevant animal models such as pigs, monkeys, or hairless guinea pigs. Such a study would provide the "link" between urine PNP and dose. In addition, a subchronic toxicity study (in rats) designed to determine a dermal Rfd would provide valuable data for risk assessment.

It must be realized that oral to dermal route extrapolation reflects two differences: (1) slower dermal absorption and (2) different first-pass metabolism. Dermal absorption is nonlinear and saturates at high doses. Another difference is that oral subchronic studies are 90 days continuous exposure. The rodent no-observed-effect level (NOEL) presently used to establish RfD is based on a continuous oral exposure to MP. On the basis of data presented, dermal absorption is probably four times less than oral and thus, a dermal NOEL should also be lower. This assumption needs to be validated by a rodent dermal subchronic toxicity trial. In the human MP exposures, limited urine PNP monitoring results provided to the work group demonstrated fluctuating levels, which suggests intermittent exposures to household MP. Because the rat subchronic toxicity trials were continuous gavage feeding and the human exposures may be intermittent, the safety factor related to exposure may be conservative. This assumption also needs to be validated by better PNP monitoring data.

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Issue: Decontamination Criteria

The proposed criteria do not address the decontamination of environmental surfaces that may be sources of exposure. The criteria rely on repeated urine analyses as a basis for determining exposure and, by inference, the potential for future exposure above criteria after urine sampling has terminated. In EPA's removal program, decontamination criteria are used that identify an indoor surface level (using a wipe sample) that "triggers" a decontamination procedure regardless of the urine PNP findings. Such criteria would supposedly add a margin of safety against the failure of urine analyses to predict future exposure and to protect more susceptible potential future occupants. Are such criteria needed and, if so, what would be the basis for establishing quantitative criteria? Also, if decontamination criteria were established, what level of MP should be achieved to declare a residence decontaminated?

The work group recognizes the possibility that biomonitoring of urinary PNP may have some false negative results. The Center for Environmental Health Laboratory that is conducting these analyses reports that, in approximately 1 out of every 200 samples, interfering substances in the urine (as yet unidentified) may prevent detection of urinary PNP. To minimize this possibility, we recommend that in certain circumstances (where there is an imminent hazard of exposure leading to poisoning), relocation criteria should be modified to include consideration of environmental sampling results in the absence of elevated urinary PNP results.

Recommendations

1. In imminent hazard situations, the local public health agency should have the flexibility to advise relocation on the basis of environmental sampling alone, even in the absence of elevated urinary PNP results. An imminent hazard situation is defined as environmental MP contamination that could reasonably result in acute MP poisoning (OP syndrome with cholinesterase inhibition) in a member of the household. A documented case of OP poisoning of household members or pets in an MP-contaminated household should serve as presumptive evidence of an imminent hazard situation.

2. Local public health agencies should also have the flexibility to increase the frequency of urinary PNP biomonitoring if they suspect the possibility of false negative results.

3. Rechecking urinary PNP after members of a household reoccupy a remediated residence would add an additional safeguard to the adequacy of remediation. Whether testing needs to be a continuing practice would be determined by examining the data on postremediation urinary PNPs as they become available.

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Issue: Clinical Evaluations as a Component of Response

What should be the appropriate triggers for clinical evaluation of persons potentially exposed to methyl parathion?

1. Symptomatic illness suspected to be related to methyl parathion may often include patients with only nonspecific symptoms. This pattern is expected to be predominant with chronic/subacute exposures. Testing does not necessarily have to be performed systematically by the agency. The agency may decide to target high-risk groups only. Information should be provided to others who want testing to take to their own providers.

2. In certain cases, individuals with confirmed exposure based on environmental testing may request clinical evaluation even if asymptomatic. Such individuals should be dealt with on a case-by-case basis. For example: Inhabitants of a home that has been treated with methyl parathion at levels that require minimal intervention are asymptomatic. However, another resident of that home may be symptomatic and has tested positive for significant exposure. The asymptomatic individual may request evaluation.

3. High-risk individuals identified by urine monitoring or environmental monitoring criteria: Group I should also be clinically evaluated. Agencies should consider systematically screening those evacuated from their homes. Logistics of this screening may depend on local resources. A self-administered questionnaire could be used.

Should an individual's health status be used as a criterion for response either independently or in conjunction with environmental or urine monitoring results?

Only if the person meets well-defined clinical criteria for poisoning: markedly depressed cholinesterase levels. For screening purposes, a cholinesterase level would be considered markedly depressed if it falls below the laboratory reference range. Because MP appears to somewhat preferentially inhibit RBC cholinesterase, this decision should be based primarily on the RBC enzyme. Plasma cholinesterase is depressed below the reference range in up to 3% of the U.S. population who are heterozygous for a genetic variant of that enzyme. In cases where screening tests are ambiguous, follow-up testing should be done. Special consideration should be given to individuals in high-risk groups.

What measure should be taken to increase the environmental medicine capability of the local health care establishment to respond appropriately and to recognize the adverse health consequences of methyl parathion exposure?

Preferably, arrangements should be made with regional occupational health specialists, for example, the Association of Occupational and Environmental Clinics (AOEC).

Direction and support can also be given to patients and medical providers through telephone support from the regional poison control centers and the National Pesticide Telecommunication Network; poison centers have the advantage of being available around the clock 7 days a week. The disadvantage of this recommendation is that it might require funding and would represent an additional agency requiring information on details of clean-up procedures and protocols. Liaisons with national or state organizations (i.e., the American Academy of Family Physicians), and arrangements to include such groups on the agenda of state or national meetings would also be useful.

Information to local providers as a secondary alternative:

• on-site by recognized experts in organophosphate exposure (i.e., grand rounds, local medical society meetings)
• videoconferencing
• availability of recognized experts by telephone contact, if needed at the discretion of the health care provider, on a case-by-case basis
• continuing medical education presentations, written material (such as ATSDR's OP case study); audiocassettes; web pages; medical society meetings; journal newsletters of local medical society; medical licensing board newsletters

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Example of Detailed Protocol/Practice Standard for Physicians
Diagnostic and Laboratory Evaluation

Definitive diagnosis must be made on the basis of a history of exposure and serial blood test of RBC cholinesterase. Until further information is available about urine PNP levels and its relationship to clinical effects, short- and long-term medical management needs serial RBC cholinesterase level, well-recognized as the "gold standard" in organophosphate exposure.

We recommend that subjects be tested under the following circumstances:

In situations where a high prevalence of OP poisoning is present or is strongly suspected (e.g., an illness outbreak or a group of applicators routinely handling OPs), or if subjects live in a home that has been identified as Level 1 (high environmental exposure), a single cholinesterase test within the laboratory normal range may not be sufficient to rule out poisoning, given the wide range of normal values in the population. In this situation, the diagnosis should be made by comparing a baseline value with serial follow-up tests, or by testing for regeneration of the native acetylcholinesterase enzyme following in vitro treatment of a blood sample with the cholinesterase antidote protopam. There is no clear evidence as to what level of cholinesterase inhibition is necessary to produce symptomatic illness, although claims have been made for various thresholds (e.g., 50% depression, or 80% depression) in the past on the basis of different case series. Variation in the degree of inhibition required to produce symptoms is related to the rate of inhibition.

Ongoing urinary PNP levels may be obtained in conjunction with the cholinesterase levels as a means of monitoring relatively acute additional methyl parathion exposure (i.e., on returning people to a contaminated home), methyl parathion metabolism, and its elimination from the body.

For chronic exposures to methyl parathion, it is likely that a high degree of inhibition would be required to produce symptoms and may be identified by a single test compared with laboratory reference ranges. The compound has some tendency to preferentially inhibit RBC ChE to a greater extent than the plasma ChE. Follow-up testing can be done when borderline normal results are obtained from the screening tests. Two to three weeks may be sufficient interval for follow-up testing for RBC cholinesterase, with monthly follow-up samples for 3 months. Weekly samples to discern a trend are an alternative.

Standardizing ChE Lab Data

Methods for monitoring ChE activity include Ph (Michel), BMC Reagent Set or BMC kit (Ellman-Boehringer), DuPont ACA, and Kodak-Ektachem. Results obtained by the different methods cannot be directly compared because of variations in reporting units and underlying test methodology. These variations cause problems when baseline samples are analyzed using one method at one lab and follow-up samples are analyzed at another (e.g., at time of illness). In clinical situations, the use of differing baseline and follow-up methods appears to be frequent. When records of OP-related illness reported to the California Pesticide Illness Surveillance Program (PISP) between 1982 to 1990 were reviewed, 123 (44.4%) of the 277 cases with multiple cholinesterase tests included samples analyzed by at least two different test methods and different population normal ranges. It is preferable that all labs analyzing ChE for MP evaluations use identical methodology.

Sample handling protocols--time to separate RBC/plasma and refrigerate samples--should also be standardized.

Treatment

Most of the exposed patients encountered so far in the recent targeted communities do not require hospitalization. For illnesses that do not require hospitalization (about 73% of definite-probable OP poisonings reported in California), decontamination of skin may be the principal treatment required. Return to activities that do not involve OP exposure is appropriate in the absence of significant impairment.

Antidotal treatment is usually reserved for hospitalized patients. Atropine reverses muscarinic symptoms (e.g., respiratory and gastrointestinal [GI] tract secretions, bradycardia) of OP poisoning for relatively short periods (pharmacologic half-life=70 minutes + 30). One to two milligram (mg) intravenous (IV) doses may be used in place of the 0.5-1.0 mg doses used in treating symptomatic bradycardia associated with heart disease. Serious doses may be titrated to maintain clear breath sounds and a heart rate of 80-100 beats/minute. Protopam (2-PAM) breaks down the cholinesterase-OP complex when 1 gram (g) is given over 10-20 minutes intravenously (after taking diagnostic cholinesterase samples). It is effective against nicotinic, muscarinic, and central nervous system (CNS) poisoning symptoms.

In the most severely ill patients, oxygen, clearance of secretions, and artificial ventilation may be required in addition to antidotal therapy. For such patients, use of morphine, aminophylline, and phenotiazines are contraindicated because of the increased risk of cardiac arrhythmia. Atropine should not be given until adequate ventilation has reversed hypoxia. These intensive care measures are more typically required following deliberate or accidental ingestion of organophosphates than for occupational illness. Treatment is not expected to be an issue for most MP exposure cases.

Non-ChE effects. In addition to ChE inhibition, many organophosphates are associated with irritation of the skin and upper respiratory tract. The agents producing odor and irritant effects associated with most OPs are thought to be low molecular weight mercaptans and sulfides. Monitoring studies of communities near application of OP cotton defoliant tributyl phosphorothioate (DEF) have demonstrated, for example, that the concentration of butyl mercaptan ranged from 0.29-9.93 parts per billion (ppb) (well above the odor thresholds for mercaptans), although concentrations of the active ingredient were orders of magnitude less (0-0.034 parts per trillion [ppt]). The odors associated with OPs often give rise to characteristic irritant symptoms, but they also provoke nonspecific systemic symptoms such as headache and nausea. Although most of the respiratory irritation is confined to the upper airways, occasional complaints of OP-associated wheezing and chest tightness are reported. These cases require careful evaluation, because bronchoconstriction sometimes results from systemic poisoning as well as airway irritation. Persistent reactive airways have occasionally been reported following exposure to OPs independent of cholinesterase inhibition. Pre-existing asthma is a risk factor for persistent symptoms. Sealants used in the remediation process should be evaluated for possible triggers of persistent reactive airways symptoms. If considering the possibility of reactive airways, you should refer such cases to those expert in such evaluations.

Delayed neuropathy and neurobehavioral effects of OPs

The most serious non-ChE-related effect of OPs is organophosphate induced delayed neurotoxicity (OPIDN), which becomes apparent 7-14 days after exposure. Historically, OPIDN has been principally associated with a handful of OP compounds that have a high propensity for inhibiting neuropathy target enzyme (NTE). These include compounds no longer registered, such as leptophos and EPN. Most OPs have the capacity to produce OPIDN following massive intoxication, but none of the currently used OPs preferentially inhibit NTE at doses that do not also cause ChE inhibition. It does not seem probable that chronic household exposures to methyl parathion are likely to produce this syndrome. Nevertheless, physicians evaluating patients should consider appropriate evaluation with nerve conduction tests, vibrometry, and electromyograms (EMGs) in patients with unexplained peripheral motor weakness or an unexplained, abnormal sensory examination of the extremities. Treatment of delayed neuropathy is supportive. Administration of atropine or pralidoxime initially or later does not influence the course of neuropathy. NB: The Risk Identification/Workgroup agrees with the Clinical Practice Workgroup that peripheral neuropathy caused by MP exposure in this setting is highly unlikely.

Occurrence of persistent neurobehavioral effects following recovery from OP poisoning is controversial. The study conducted by Savage demonstrated deficits in memory and abstraction

on test batteries, but normal neurological examinations. Rosenstock demonstrated several deficits with the WHO test battery and also subclinical decreases in vibrotactile sensitivity, but also reported normal clinical examinations. The test batteries conducted by Steenland showed deficits in two neurobehavioral tests (sustained visual attention and mood scales) and decreased vibrotactile sensitivity in the toe, but neurological examinations were again normal.

Clinical note: Neurobehavioral testing is a research tool not routinely conducted in individual clinical cases of organophosphate exposure or overt poisoning.

Background: classical high-dose acute poisoning

Organophosphates (OPs) poison the nervous system by inhibiting the breakdown of the transmitter acetylcholine by the enzyme acetylcholinesterase. This results in overstimulation of portions of the nervous system that contain acetylcholine: muscarinic--postganglionic fibers of the parasympathetic nervous system (control secretions of respiratory and GI tracts, heart rate, etc), sweat glands in the sympathetic nervous system, preganglionic fibers in the sympathetic nervous system, and skeletal muscle. The acronym MUDDLES is a helpful means of remembering the principal effects of cholinesterase inhibitors:

Mioses
Urination
Diarrhea
Diaphoresis
Lacrimation
Excitation (of CNS)
Salivation

Other effects of note include bradycardia (slowing of the heart rate). This effect may be quite severe in some instances and may be responsible for episodes of dizziness and syncope (fainting) associated with organophosphate poisoning. These same symptoms may be produced by inhibition of acetylcholinesterase in the central nervous system, so that it is frequently impossible to ascertain the physiologic cause of the symptoms in individual cases.

Outline of Suggested Medical Evaluation

Questionnaire (must be standardized for all those undergoing evaluation)

A standardized questionnaire should have relatively easy capability of having data entered in a computerized database for future reference.

General health information

Need to discern pre-existing conditions that may mimic and therefore, be possible confounders in symptoms that would be seen in organophosphate overexposure.

• CNS (migraine, other headaches, depression, anxiety syndromes)
• Peripheral nervous system problems (from such conditions as diabetes, alcoholism, thyroid disorders, carpal tunnel syndrome, vitamin deficiencies)
• GI (irritable bowel, chronic diarrhea, malabsorption, inflammatory bowel)
• Respiratory (asthma, smoking, reactive airways)
• Psychological (chronic anxiety, depression)
• Occupational history
• Environmental history (home use of pesticides/gardening)

Exposure History

Anecdotal information about potential exposure

Dates of spraying

Times at residence; number of people in residence at time of spraying

Activities in residence likely to increase exposure of certain individuals (walking without shoes; crawling infants; homebound individuals)

Any acute symptoms

Symptoms Present

Relatively Specific Symptoms: hypersalivation, bradycardia in absence of cardiac disease, inappropriate sweating, muscle fasciculations, excessive urination (can be confused with urinary tract infection [UTI])

Nonspecific: headache, nausea, abdominal pain, diarrhea, trouble concentrating, blurred vision, metallic taste, wheezing, coughing

Irritant: odor, stinging eyes, nose/upper respiratory tract, skin paresthesia, skin rash

Physical exam: general physical status, orientation; blood pressure, heart rate, respiratory rate, temperature, pupillary exam; cranial nerves; pharynx

chest: wheezes, rales
abdomen: tenderness
extremities: reflexes; pinprick sensation; vibration

Additional Lab: Unnecessary for organophosphate exposure evaluation; however, to further evaluate other medical conditions, may do additional testing at the discretion of the physician: CBC, chem panel, UA: (PFTs/methacholine not indicated unless index of suspicion for RADs; see above)

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