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4 Risk Characterization in this chapter, the National Research CounciT's (NRC's) subcommittee on methyl bromide considers the material covered in Sections IV and V of the California Department of Pesticide Regulation's (DPR's) risk characterization document. in Section rv, "Risk Assessment," DPR justifies the selection of the toxicological endpoints and the critical no-observed-adverse-effect levels (NOAELs) used in the risk characterization, presents the exposure assessment in the form of tables of exposure measurements for different occupational and residential exposure categories, and presents margins of exposure for each of those categories based on the critical NOAELs and the exposure measure- ments. in Section V, "Risk Appraisal," DPR addresses the uncertainties in the toxicological and exposure databases, discusses the factors used for intra- species and interspecies extrapolation, and discusses issues related to the Food Quality Protection Act. RISK CHARACTERIZATION GOALS As defined by the NRC (1994) "risk characterization combines the assess- ments of exposure and response under various exposure conditions to estimate the probability of specific harm to an exposed individual or population. To the extent feasible, this characterization should include the distribution of risk in the population." To properly perform a risk assessment, the hazard posed by the agent must be assessed in terms of the adverse health effects it can 56
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RISK CHAR 4 CTERIZ~4 TION 5 7 cause, the dose-response must be characterized, and the intensity, frequency, and duration of exposure should be determined. The quality of information available for each of these risk characterization components governs the qual- ity of the eventual estimate of risk to individuals by the use of methyl bro- mide. DPR has addressed each ofthese risk assessment components in its risk characterization document. In the sections below, the subcommittee reviews DPR's presentation of the information it gathered and analyzed in assessing the risk to agricultural workers and the general population from methyl bro- mide exposures. HAZARD IDENTIFICATION DPR has presented a substantial amount of experimental information on the toxicology of methyl bromide, including the response to various concentra- tions of the chemical. A number of observations in humans following methyl bromide exposure have been made but preclude a determination of a dose- response relationship. Furthermore, the actual absorbed dosage of methyl bro- mide is difficult to determine in either animal studies or reports of human exposure. Obviously, in the absence of true dose-response information, the concentration-response is a usable guide for judging, with high confidence, the ambient levels of the chemical that can be expected to represent no harm to humans. Acute Toxicity Database The database for the derivation of an acute reference concentration (RfC) includes a single exposure inhalation study with the rat (Driscoll and HurIey ~ 993), a repeated exposure study with the dog (Newton ~994b), and two well- conducted developmental toxicity studies in different species, the rabbit (Breslin et al. 1990b) and the rat (Sikov et al. 1981~. In addition, there is a supporting two-generation reproductive study in the rat and pharmacokinetic studies following inhalation exposure. Therefore, the subcommittee considers the database for the derivation of an acute RfC to be good. The subcommittee believes that DPR's use of a study with repeated expo- sures (Newton 1994b) as the critical study on which to base an acute RfC for children is conservative and ensures safety. The NOAEL from a study that uses a single exposure rather than repeat exposures is sufficient to derive an acute RfC provided that there is quantitative dose-response information, the study is conducted with the most sensitive species, and there is a sufficient
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55 METHYL BROMIDE RISK CHARACTERIZATIONIN CALIFORNIA database of supplemental toxicological information. However, because the rodent study with a single exposure to methyl bromide (Driscoll and HurIey 1993) resulted in a NOAEL that was three times higher than the NOAEL de- rived from the critical study with the dog (Newton 1994b), the rodent study would have resulted in a less conservative RfC. With respect to the developmental studies by Breslin et al. (199Oa,b), the subcommittee also considered it appropriate for determining an acute NOAEL for the assessment of the risks of acute occupational and residential exposure to methyl bromide. This is plausible given that a single gestational exposure is theoretically sufficient to produce an adverse developmental effect (EPA 1991), particularly blockage of galIbladder development (gestation day 11.5 to 12.5), which occurs over the course of approximately 24 hr in the rabbit. Furthermore, there are large numbers of women of childbearing age in the workforce. Finally, the maternal toxicity that occurred in the Breslin et al. studies (1990 a,b) should not negate the observed developmental effects be- cause gallbladder development occurred 5 to 6 days before the dams displayed toxicity and because only a minority of the dams displayed toxicity. The lowest-observed-adverse-effect level (LOAEL) (80 parts per million (ppm)) used by DPR was based on the dose at which galIbladder agenesis, fetal weight declines, and fused sternebrae were noted. The NOAEL was 40 ppm, resulting in an RfC of 210 ppb. Subchronic Toxicity Database In addition to the above-cited developmental endpoints, there were also neurotoxic endpoints selected as critical effects for both the acute and the sub- chronic time periods. These endpoints were both from a single dog study (Newton, 1994b) in which the dogs at the lowest doses showed signs of de- pressed activity and the dogs at the higher doses and longer exposure periods showed severe signs of neurotoxicity. Because neurotoxic signs are a promi- nent feature of human methyl bromide intoxication, this neurotoxicity study in the dog appears to be reasonably selected as the critical study. The acute end- point was for a NOAEL of 103 ppm, with human equivalent NOAELs of 45 ppm and 25 ppm for adults and children, respectively. Because these were higher than the human equivalent NOAEL calculated from the rabbit develop- mental study, an RfC was not calculated from this study. The database for the subchronic studies appears to be quite extensive; there were numerous studies that DPR had an opportunity to evaluate to select a critical study for subchronic toxicity. DPR's selection appears to be appropri- ate in that they selected a study performed for regulatory purposes that was
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RISK CHARACTERIZE TION 59 carefully designed and conducted according to the contract laboratory's stan- dard operating procedures. The one drawback about this study (Newton ~994b) is that it was conducted to establish dose levels for a proposed chronic study (which was subsequently not performed) and not originally planned as a foam subchronic study. As a result, there were decisions made midway through the study by the authors to change the study design with respect to duration or dose levels. There were only four dogs of each sex per treatment group, which is a very small number of replications. The critical observation was made outside the standard operating procedures by a trained veterinarian on two female dogs only, which leaves the observation somewhat equivocal. However, to be conservative, the subcommittee agrees that this still appears to be the most suitable critical study out of a total of 26 studies presented as pos- sibilities by DPR. On the other hand, the subcommittee notes that if these observations on the two dogs at 5 ppm are not considered real manifestations of methyI-bromide-mediated neurotoxicity, selection of another study (e.g., Sikov et al. 1981) as the critical one would raise the NOAEL by approxi- mately an order of magnitude, that is, to 20 ppm (see Table 2-~. The subchronic estimated LOAEL of 5 ppm is equivocal because of the lack of a dose-response curve at the lower dose levels, the observation of de- pressed activity in two of eight dogs outside the standard protocol procedures, and the low number of replications. However, the seriousness of the neuro- toxicity observed in humans and the potential long-term nature of the neuro- logical effects makes this equivocal observation reasonable as a conservative endpoint. Chronic Toxicity Database The existing database identified by DPR for derivation of an RfC for chron- ic toxicity includes two well-conducted chronic studies with different species, supported by subchronic studies in several species, a two-generation repro- duction study, other data on developmental and reproductive effects, and pharmacokinetic studies employing inhalation exposure. The subcommittee considers the database available for derivation of a chronic RfC for methyl bromide good and neither of the key studies had major inadequacies. The chronic LORES (3 ppm) used by DPR was based on the lowest dose that caused changes in the olfactory epithelium in rats exposed to methyl bro- mide for 29 months (Reuzel et al. 1987, 1991~. No effects were observed in the kacheobronchial or pulmonary regions of the respiratory Fact and no other exposure-related effects were noted at this concentration. The LOAEL was 30 ppm for all other more adverse effects. The NOVEL and LOAEL for
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60 METHYL BROMIDE RISK CHARACTERI~4TIONIN CALIFOR~IA respiratory effects, and also for all other effects, in the NIP study (1992) with mice were 33 ppm and lL00 ppm, respectively. The critical endpoint selected from the Reuzel et al. study (1987) is appropriate as more pronounced nasal lesions have been observed at higher concentrations in shorter-term studies (Eustis et al. 1988; Hurtt et al. 1988~; however, the critical endpoint in this case is observed at increased incidences only in aged rats, making it an equiv- ocal endpoint. The Hurtt et al. (1988) study indicated that the lesions observed after exposure to methyl bromide at 200 ppm, 6 hr/day for 105 days, were largely reversible. Another consideration is the endpoint of reduced growth of neonatal rats. The NOAEL and LOAEL for reduced growth of neonatal rats in the two-generation reproduction study by American Biogenics Corporation (1986) were 3 and 30 ppm, respectively. Therefore, the Reuzel et al. study (1987) has the lowest LOAEL ofthe studies considered appropriate for deri- vation of the RfC. The subcommittee agrees with DPR's choice of this end- point, with the notation that at the 3-ppm concentration the effects are mild and increased incidences (but not necessarily severity) are observed only in aged rats. Developmental Neurotoxicity Methyl bromide is clearly a neurotoxicant in human adults; neurotoxic signs are prominent following high-level human exposures and one study sug- gests that mild neurotoxic effects might also occur at Tow levels (Anger et al. 19861. Methyl bromide also is a developmental toxicant as indicated by labo- ratory animal studies. Therefore, there is reason to suspect that methyl bro- mide could be a developmental neurotoxicant, which suggests that data from a developmental neurotoxicity test would be informative to the risk assess- ment. However, the subcommittee finds that the developmental neurotoxicity test, as it is currently described in the U.S. Environmental Protection Agency (EPA) guidelines (EPA 199 T), might be inadequate to identify and character- ize specific developmental neurotoxicants. Therefore, the utility of data from such a test for DPR's regulatory needs is unclear, and the subcommittee finds that the risk characterization conducted on the currently available database by DPR is probably sufficient for identifying appropriate NOAEI,s. EXPOSURE ASSESSMENT Although DPR has assembled a large data set of occupational exposure studies for methyl bromide, the exposure assessment based on that data set
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RISK CHARA CTERIZA TION 61 has a number of shortcomings. First, the methyl bromide concentrations in air are compromised by the lack of a robust analytical method for making such measurements. Although the 50°/O recovery adjustment used by DPR appears to be reasonable for many of the samples, the subcommittee considers it likely that the actual concentrations in air are underestimated rather than overesti- mated. The measured exposure data for any one occupational exposure cate- gory are variable and sparse and nonexistent for residents living near fumi- gated fields. For approximately one-third of the exposure groups assessed, the data consist of a single measurement. The variability in the exposure mea- surements reflects the inherent variability in environmental measurements as well as the lack of a comprehensive and systematic sampling program. The subcommittee realizes that DPR was constrained to work with the available monitoring data that was often collected by outside parties, such as growers and manufacturers, for different purposes. In the exposure assessment, DPR uses various categories of exposure, in- cluding acute (24-hr), short-term (7-day), seasonal (subchronic), and chronic. DPR's treatment of these durations and the subcommittee's consideration of them is presented below. Appropriateness of Acute-Exposure Definition DPR's use of an acute (24-hr) exposure period is more reasonable for the residential exposure scenario than for an acute occupational (Bohr) exposure scenario. Some individuals, such as infants, young children, or elderly per- sons, might indeed spend most of a given 24-hr period inside the residence. However, it is unlikely that a worker will be exposed for 24 hr. For the occu- pational acute-exposure scenario, a shorter duration approximating the length of a work shift (8 hr) would have been more appropriate. This is particularly true for the exposure assessments and the margin of exposure analyses. For example, from the acute neurotoxicity study in dogs (Newton et al. 1994a,b, summarized in Table 3 of DPRi999,p. 42), it can be seen that a 24-hr expo- sure to 50 ppm would not be the toxicological equivalent of a 6-fur exposure to 200 ppm. In dogs, a 24-hr exposure to 50 ppm is well tolerated, whereas a 6- hr exposure to 200 ppm would likely cause acute neurological signs. This becomes even more problematic for very short exposures. The 24-hr time- weighted average of a 1-fur exposure to 1,200 ppm is also 50 ppm, but based on the dog neurotoxicity study and the LCso data presented in Table ~ of the DPR report (p. 35), this is likely to be a lethal exposure for at least some of the animals. The subcommittee believes that humans would not respond dif- ferently from laboratory animals in this regard.
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62 METHYL BROMIDE RISK CHARA CTERIZA TION IN CALIFORNIA As a practical matter, because DPR normalized both the methyl bromide concentrations from the exposure assessment studies and the methyl bromide concentrations from the toxicity studies to 24 hr. the end effect might be that the two cancel each other out for the occupational exposure scenario, and the result might lead to a more conservative risk assessment for the residential exposure scenario. This is because the studies that DPR used to determine the critical NOAELs for acute toxicity all used exposure durations of 6 to ~ hr. DPR then normalized the NOAEL concentrations to 24 hr using concentra- tion/exposure duration relationships. Thus, the actual exposure durations used in the studies were good approximations for an acute occupational exposure, and the two normalizations essentially canceled one another out when the margins of exposure (MOEs) were calculated. On the other hand, as already mentioned, a 6-fur exposure to 200 ppm is likely to be more acutely toxic than a 24-hr exposure to 50 ppm. Thus, the 24-hr normalized NOAEL might be lower than a NOAEL derived from actual 24-hr exposures would be. Because the residential exposure measurements should be made over 24 hr. and there- fore would not have to be normalized, the MOEs for the residential exposure scenarios would be more conservative than the occupational MOEs. As dis- cussed in Chapter 3 of this report, the fact that few actual exposure measure- ments were made for the residential exposure scenarios is a separate problem with the risk assessment. Subchronic Exposure DPR defines two categories of subchronic exposure: short-term and sea- sonal. The subcommittee agrees with DPR that it is appropriate to have a subchronic exposure category to describe worker exposures in preplan" soil fumigation and commodity fumigation, and that a subchronic category might also be appropriate for residents of fumigated houses or residents who live near fumigation facilities. As outlined in Section TV ofthe DPR report (Table 19, p. 105) residents might have short-term exposures by virtue of moving back into a fumigated house. Residents may also have seasonal exposures as a result of living near fumigation facilities. The subcommittee also believes that it is plausible that residents living near fumigated fields might be exposed to methyl bromide for periods lasting longer than 24 hr. and therefore, that Section IV should include an exposure assessment for short-term and seasonal exposures to residents near fumigated fields. The subcommittee does not believe that it is appropriate to assume, based on the short half-life of unmetabolized methyl bromide, that the effects of methyl bromide are completely reversed a few days after cessation of expo-
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RISK CHARD CTERIZA TION 63 sure. The subcommittee bases this statement on the fact that toxicology stud- ies suggest that longer exposures are associated with lower NOAELs than shorter studies, indicating that some processes involved in methyl bromide toxicity are not likely to be quickly (within a few days) or completely revers- ible. Therefore, the subcommittee concurs with DPR that the seasonal expo- sure category is an appropriate one for workers who have repeated exposures to methyl bromide, separated by periods up to several days, over the course of a season. As stated in Table ~ 5 (DPR ~ 999, p. 92) and the description of the exposure durations in the DPR report (DPR 1999, p. 10), the durations for the short- term and seasonal scenarios appear to be ~ week and 6 weeks, respectively. These are the treatment durations at which effects were observed in the two critical subchronic studies identified by DPR (Sikov et al. ~ 981; Newton et al. 1994b). However, elsewhere in the document, DPR states that the seasonal exposure duration is "greater than one month" (DPR 1999, p. 90), and still elsewhere as 90 days (DPR 1999, Section IV.B, p. 93~. The subcommittee believes that the appropriate duration is 90 days because the seasonal uses noted above are likely to last longer than ~ month or 6 weeks. The distinction between the duration of the critical studies and the actual durations of expo- sure for the scenarios should be clarified in Tables ~ 5 to 20. The subcommit- tee concurs with the point made in the DPR report (p. 90) that the seasonal NOAEL might have been Tower if the dogs in the critical study had been ex- posed for longer than 6 weeks (Newton et al. 1994b). However, as already discussed in this report, the subchronic RfC derived from that study is a fairly conservative one, and therefore, probably protective even for longer exposure durations. Chronic Exposure Chronic exposure generally refers to a 70-year (lifetime) continuous expo- sure to the chemical of concern. There does not appear to be chronic nonoccu- pational exposures for any populations associated with field agricultural appli- cations, because the application of methyl bromide is on a seasonal basis, not year round. However, the subcommittee believes that chronic nonoccupation- al exposures could be possible for residents near commodity-fumigation faciT- ities or transport facilities, where fumigation of commodity storage ware- houses or shipping containers might occur on a year-round basis. Fumigation workers also might have chronic exposures. The subcommittee believes that DPR's normalization of the 6 hr/day, 5 days/wk, exposure of the lifetime study for rats to a 24-hr/day lifetime expo-
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64 METHYL BROMIDE RISK CHAR)4CTERIZATIONIN CALIFORNIA sure for humans is appropriate, but notes that it adds another layer of conser- vativeness to the derived value. The RfC should be applied to lifetime expo- sures. The subcommittee disagrees with DPR's definition of chronic exposure for humans as "a year or more" (DPRI999,p. 4), because this definition does not agree with the accepted EPA definition (EPA 1989) of chronic exposure as a period between 7 years (approximately 10% of a human lifetime) and a lifetime. Subchronic exposures are defined by EPA as ranging from several months to several years. MARGIN-OF-EXPOSURE ANALYSIS DPR has done a tremendous amount of work in pulling together a very large amount of exposure information to compare with methyl bromide con- centrations and durations of toxicological concern. DPR has chosen to use an MOE, a ratio of the critical human equivalent NOAEL to the estimated human exposure levels, to characterize the risks posed to agricultural workers, nearby residents, and residents returning to fumigated homes. Nevertheless, the MOE analysis is one of the least satisfying aspects of the DPR document. The risk characterization document, as reviewed by the subcommittee, con- tains neither a statement of DPR's information objectives or data needs, nor does it indicate how the MOE methodology used is related to those needs. There is minimal quantitative treatment of variability and no apparent quanti- tative analysis of uncertainty (both discussed below). The subcommittee be- lieves that it is critical that DPR explicitly state how these important issues could affect the analysis to produce information that is helpful for decision- making. DPR appears to be using the exposure data to make a large number of binary comparisons (e.g., safe and dangerous) directly from the observed data, with adjustments to the maximum permissible application rate, and as- sumptions about the repetition of exposures from day to day. The level of concern for safe or dangerous exposure is an MOE of 100; when MOEs are greater than 100, the populations are assumed to have little risk of adverse effects, and when the MOEs are less than 100, there is a cause for concern for potential adverse effects. DPR appears to be asking, "Do the single-day expo- sure data that have been directly observed for particular groups, such as appli- cators, indicate that when methyl bromide is used at the maximum permissi- ble application rate, these workers or residents will be exposed to concentra- tions that provide a less than a 100-fold margin below the projected human- equivalent NOAEL for acute exposures (21 to 45 ppm)?" and "Do the acute exposure data indicate a less than 100-fold margin for the longer-term end- points based on DPR's assumptions for weekly and seasonal exposures?" In all, the Tables 16-19 (pp. 96-105) of the DPR report give exposure data for
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RISK CHARD CTERIZA TION 65 160 different worker and residential groups, and an additional five cases are based on modeling. Even within a specific exposed group, exposure levels for a particular duration are both considerably variable and, depending on the database, uncertain. "Variability" in modern risk assessment is defined as real differences among cases (sullen and Frey 1999; Hattis and Anderson 1999; Hattis and Barlow 1996; Hattis and Burmaster 1994; Thompson 1999~. Breaking the data down into different kinds of exposed groups, as in DPR's set of 160 ex- posure categories, addresses one source of variability. However, characteriz- ing the real variability in exposures experienced by different people within an exposed group is also critical for an informative risk evaluation. This espe- cially applies for a toxicant with a highly upward turning nonlinearity in its population dose-response curve because the individuals at the high-end con- centration of the exposure distribution are generally at much larger potential risk for more serious adverse effects than more typical members of the ex- posed group. Variability in exposures is usually characterized by some mea- sure of dispersion, such as the geometric standard deviation for usual unimod- al lognormal distributions. "Uncertainty," in contrast, reflects the imperfection in our knowledge about the true value of a parameter- including parameters characterizing variability. Uncertainty can be reduced by better and more extensive data, improved mod- els, and so forth. Characterizing uncertainty is important in a risk analysis to frankly convey how confident the audience should be in the results and con- clusions presented. Commonly used measures of uncertainty include the stan- dard error of the mean or the standard error of the estimate of a regression coefficient in a standard multiple regression analysis (sullen and Frey 1999; Hattis and Anderson 1999; Hattis and Barlow 1996; Hattis and Burmaster 994; Thompson ~ 999~. Of the ~ 60 worker categories presented, the exposure estimates for 59 cate- gories are based on a single air-concentration measurement; 43 categories are assessed based on only two measured air values, and the remaining 58 catego- ries had more than two measurements. The subcommittee finds that the treat- ment of data from worker and general population groups with these differing amounts of data is neither consistent nor designed to produce useful estimates of exposures of concern with respect to variability and uncertainty. The sub- committee comments on each of these cases below. Categories with More than Two Data Points DPR has summarized acute exposures for worker categories when there are more than two data points as the range of the data directly observed (after
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66 METHYL BROMIDE RISK CHARACTERIZATIONIN CALIFORNIA adjustments for such things as application rates) plus a simple arithmetic mean and arithmetic standard deviation. However, DPR did not appear to calculate a consistent percentile from the observed data. In the current analy- sis, DPR has implicitly treated with greater conservatism cases in which there are more data points (a higher percentile is used) than cases in which there are fewer data points. Moreover, basing calculations on the highest of N values introduces statistical instabilities into the analysis. Finally, DPR has not pro- vided a rationale for their choice of arithmetic means and arithmetic standard deviations, rather than more typical Tognormal statistics. Analyses of data for some groups (e.g., copilots, applicators, tarp removers) by the subcommittee (see Appendix C) indicates that in general Tognormal distributions would be more appropriate than would normal distributions, as is usual for exposure distributions. (For further discussion of the use of logno~al distributions for describing the variability in exposures, see Cullen and Frey (1999~; Hattis and Burmaster (l 994~; Thompson (1999~.) Categories with One or Two Data Points In most cases, DPR has calculated a mean (if there were two points) and listed the higher of two points as the high value. However, in some other cases, a "95~ percentile" value is calculated by assuming an arithmetic stan- dard deviation equal to the mean of the one observed data point. DPR does not explain why this is done for some single-point exposure categories and not others. For cases in which there are only one or two data points, the subcom- mittee encourages DPR to either gather additional data or consolidate related exposure categories on an a priori basis (i.e., not based on the measured levels but based on similarity of the processes generating the exposures) to assemble greater numbers of data points for basic statistical treatment within groups. UNCERTAINTY ISSUES In Section V, "Risk Appraisal," of the DPR report, DPR discusses the limi- tations of its risk characterization for methyl bromide and how it quan- titatively and qualitatively dealt with the specific uncertainties The subcom- mittee comments upon these limitations and DPR's approach to them below. Derivation of Reference Concentrations DPR has developed inhalation RfCs for acute, subchronic, and chronic ex- posures. When derived from NOAELs, the RfCs reflect 100-fold uncertain-
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RISK CHARD CTERIZA TION 67 ties, with a 10-fold uncertainty for species differences and a 10-fold uncer- tainty for variations among humans. When NOAELs were estimated from LOAELs, a ~ 0-fold uncertainty was used. DPR states that it is their policy to use a default ~ 0-fold uncertainty factor to estimate a NOAEL from a LOAEL. The subcommittee in general agrees with this application of a default uncer- tainty factor of 10, particularly where the endpoint is an adverse effect such as neurotoxicity or developmental toxicity. In the case of the chronic RfC, the LOAEL was so mild as to be close to a NOAEL. In that case, the subcommit- tee suggests that a three-fold uncertainty factor be considered. However, the subcommittee realizes that DPR is constrained to have a chronic RfC no high- er that the EPA's chronic RfC of 1.3 ppb. Therefore, DPR's chronic RfC for adults of 2 ppb is reasonable. The subcommittee also agrees that the inter- species and intraspecies uncertainty factors of 10 (for each) applied to the acute and subchronic RfCs are appropriate. The subcommittee notes that DPR used an older method than EPA's cur- rent method for the derivation of its RfCs (EPA 1994~. DPR derived separate values for adults and children; this is not possible with the current EPA method. It is interesting to note that although different methodologies were used, the RfCs derived by DPR for adults and children, 2 ppb and 1 ppb, re- spectively, are similar to EPA's value of 1.3 ppb. Sensitive Subpopulations The Food Quality Protection Act of 1996 mandated that the EPA use an additional 10-fold safety factor for infants and children, unless it could be determined from available data that a different factor would be safe. The sub- committee considered the methyl bromide database in light of the three crite- ria used by EPA to determine the safety factor. The first criterion concerns the completeness and reliability of the toxicology database. As discussed at length in Chapter 2 and earlier in this chapter, the subcommittee finds that the toxicology database for methyl bromide was good overall. The second crite- rion concerns the completeness and reliability of the exposure database. As discussed in Chapter 3, the exposure database, though flawed, is quite exten- sive for occupational exposures. in contrast, for residential exposures, the category into which most exposures to children and infants would fall, the database is inadequate. Limited data are available only for residential expo- sures during fumigation of the residence, not for residents living next to fumi- gated fields or fumigation facilities. The final criterion concerns the potential for prenatal and postnatal toxicity. The two-generation rat reproduction study (American Biogenics Corporation 1986) and the rabbit and rat developmental toxicity studies (Breslin et al. ~ 990a,b; Sikov et al. ~ 98 I ) indicate that methyl
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6S METHYL BROMIDE RIsK CHOW CTERIZA TION IN CALIFORNIA bromide is not a potent teratogen, but that it can cause developmental toxicity. The teratogenic effect, gallbladder agenesis, is considered to be a minor mal- formation and this effect was seen only at doses that caused maternal toxicity. The subcommittee expects that a potent teratogen would cause multiple mal- formations at doses that do not cause maternal toxicity. As noted in the DPR report, there is some evidence for increased sensitivity of the developing or- ganism to adverse effects of methyl bromide compared with the mothers in rats (American Biogenics Corporation 1986), but not in rabbits (Breslin et al. ~ 990a,b). Although good otherwise, the reproductive and developmental da- tabase lacks a developmental neurotoxicity study. According to DPR (DPR 1999, p. 126), EPA has added an additional uncertainty factor of 3 in the ab- sence of such a study in its recent time-limited tolerances for pesticides. Given that the NOAELs used for the various exposure scenarios are already quite conservative, the subcommittee felt that an additional safety factor for infants and children was not necessary. Multiple Exposures Although DPR acknowledges that workers might receive multiple expo- sures from methyl bromide, there is only a limited discussion on the potential exposure of residents who live in areas where multiple fields might be fumi- gated simultaneously or within a short period of time. Because the majority of methyl bromide is used in field applications, residents near treated fields are subject to frequent exposures during the fumigation season. The subcom- mittee notes that it would be unrealistic to assume that most residents in agri- cultural areas live near only one treated field. Therefore, the buffer zones established by DPR to be protective of residents adjacent to one field might not be sufficient should the residents be near multiple treated fields. Although these exposures were commented upon in Chapter 3, the subcommittee reiter- ates that this is a significant data gap in the exposure assessment. In addition, the subcommittee has concerns regarding repeated exposures of workers, such as soil or structural fumigators, because soil fumigators might have repeated exposures on consecutive days for several months or structural fumigators might be engaged in multiple fumigations on a single day (Anger et al. 1986~. The potential that such repeated exposures might occur raises concerns in light of results from Anger et al. (1986) that suggest that relatively low exposure levels (<2 to 3 ppm) of methyl bromide from fumigation might produce slight neurotoxic effects in workers. Additional data on the neurotoxic effects of methyl bromide in exposed workers are needed.
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RISK CHAM CTERIZA TION 69 The proposed regulations provide for a 36-hr waiting period between the application of methyl bromide to a field near a school and when school is in session. In practical terms, this means that fumigation of fields near schools are limited to Friday evenings and Saturday. However, DPR makes no provi- sion for school activities that might occur during weekends at the school, par- ticularly outdoor activities such as sports. Such exposures should not be ig- nored, because children might have greater susceptibility to effects from methyl bromide exposures, and because data suggest that slight neurotoxic effects might occur at Tow concentrations (Anger et al. 1986~. SUMMARY DPR characterized the risks associated with exposure to methyl bromide by using an MOE approach. The subcommittee found this approach to be rea- sonable for determining which workers or residents are likely to be exposed to potentially harmful methyl bromide concentrations. However the subcommit- tee had concerns about DPR's use of MOEs for risk characterizations and for protecting nonworkers, in particular, people living near fumigated fields. DPR has not indicated how the MOEs are to be used to determine the protec- tiveness ofthe buffer zones specified in the application permits. Nor has DPR characterized certain potentially sensitive populations, such as children in schools or living near fumigated fields, although the proposed regulations address the exposure of children by restricting the application times near schools. The subcommittee feels that the uncertainties addressed by DPR in the report, including extrapolating from LOAELs to NOAELs, and from ani- mals to human, although important, are only part of the uncertainties that need to be dealt with in the document.
Representative terms from entire chapter: