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Executive Summary Methyl bromide is a gaseous pesticide used to fumigate soil, crops, commod- ity warehouses, and commodity-shipping facilities. Up to 17 million pounds of methyl bromide are used annually in California to treat grapes, almonds, strawberries, and other crops. Methyl bromide is also a known stratospheric ozone depleter and, as such, is scheduled to be phased out of use in the United States by 2005 under the United Nations Montreal Protocol. In California, the use of methyl bromide is regulated by the Department of Pesticide Regulation (DPR), which is responsible for establishing the permit conditions that govern the application of methyl bromide for pest control. The actual permits for use are issued on a site-specific basis by the local coun- ty agricultural commissioners. Because of concern for potential adverse health effects, in 1999 DPR developed a draft risk characterization document for inhalation exposure to methyl bromide. The DPR document is intended to support new regulations regarding the agricultural use of this pesticide. The proposed regulations encompass changes to protect children in nearby schools, establish minimum buffer zones around application sites, require no- tif~cation of nearby residents, and set new limits on hours that fumigation em- ployees may work. TlIE SUBCOMMITTEE'S TASK The State of California requires that DPR arrange for an external peer re- view of the scientific basis for all regulations. To this end, the National Re- search Council (NRC) was asked to review independently the draft risk char- acterization document prepared by DPR for inhalation exposure to methyl 1
2 METHYL BROMIDE RISK CHARA CTERIZA TION IN CALIFORNIA bromide. NRC assigned the task to the Committee on Toxicology, which con- vened the Subcommittee for the Review of the Risk Assessment of Methyl Bromide. The subcommittee was asked to review the data, determine the ap- propriateness of the critical studies, consider the mode of action of methyl bromide and its implications in risk assessment, determine the appropriateness of the exposure assessment and the mathematical models, and identify data gaps and make recommendations for further research. THE SUBCOMMITTEE'S EVALUATION The 1999 risk characterization document prepared by DPR is a revision of a 1992 preliminary risk assessment that addressed acute inhalation exposure of residents reentering fumigated homes. The 1999 document updates the toxicity information on methyl bromide and provides a more extensive review of the worker and residential exposure data gathered by the methyl bromide manufacturers and applicators and DPR itself over the past several years. The toxicity and exposure data were combined to establish margins of exposure) for agricultural workers, residents living near fumigated fields, and residents reentering fumigated homes. The subcommittee's comments on the DPR risk characterization document and its recommendations for further studies are summarized below under three broad categories: toxicology, exposure assess- ment, and risk characterization. Toxicology The DPR risk characterization document presents information on the toxicokinetics and toxicity of methyl bromide, including its acute, subchronic, chronic, developmental, reproductive, neurological, and genotoxic effects. The subcommittee agrees with DPR that the critical target organ for acute ex- posure to methyl bromide is the nervous system. Methyl bromide also ap- pears to be a developmental and possibly a reproductive toxicant. The DPR report appropriately summarizes the available toxicokinetic data on methyl bromide in terms of its absorption, distribution and excretion, but it provides only a limited discussion of the metabolism of the pesticide. That discussion is particularly important, because in some individuals there appears Margin of exposure is a ratio of the concentration at which adverse effects occur to the estimate of concentration found in the workplace or ambient air.
EXECUTIVE SUMMARY 3 to be a more effective reaction between methyl bromide and glutathione transferase, which can alter the sensitivity of those individuals to its toxic ef- fects. Although DPR adequately reviewed the available literature on the genotoxicity of methyl bromide, it failed to elucidate the relationship between the mutagenicity of methyl bromide and its potential carcinogenicity. When possible, the DPR report identified the no-observed-adverse-effect level (NOAEL)2 or the Towest-observed-adverse-effect level (LoAEL)3 fol- lowing acute, subchronic, and chronic exposures. The subcommittee agrees with the critical studies and NOAELs selected by DPR in developing the ref- erence concentrations for acute, subchronic, and chronic exposures. For acute toxicity, DPR chose 40 parts per million (ppm) as a NOAEL based on a devel- opmental toxicity study in which rabbits exposed in utero exhibited fused breastbones and gallbladder agenesis (lack of gallbladder development). This NOAEL resulted in an acute inhalation reference concentrations (RfC) of 210 parts per billion (ppb) for humans. For subchronic toxicity, 1-week and 6- week RfCs were derived. The subcommittee supports DPR's I-week RfC of 120 ppb and 70 ppb for adults and children, respectively, based on a NOAEL of 20 ppm for convulsions, paresis, and death in pregnant rabbits. The sub- committee also supports DPR's 6-week RfCs of 2 ppb and 1 ppb for adults and children, respectively, based on a LOAEL of 5 ppm for decreased respon- siveness and spleen weight in dogs. The subcommittee notes that the reported neurotoxic effects (lack of responsiveness in two of eight dogs) seen in the subchronic toxicity dog study used to derive the 6-week RfC, because the ob- servations were not part of the study protocol and were not dramatic. Never- theless, the subcommittee believes that the reported effects may be indicative of neurotoxicity. DPR used a 29-month rat inhalation study for the derivation of the chronic exposure RfC of 2 ppb for adults and 1 ppb for children. The LOAEL of 3 ppm identified in that study was based on an increase in the number of cells and a change in cell type and function in the nasal cavity. The subcommittee 2NOAEL is an exposure level at which there are no statistically or biologically significant increases in the frequency or severity of adverse effects between the exposed population and its appropriate control. 3LoAEL is the lowest exposure level at which there are statistically or biologically significant increases in frequency or severity of adverse effects between the exposed population and its appropriate control. 4A reference concentration is an estimate of the concentration of a substance that is unlikely to cause noncancer health effects in humans during a lifetime. It is used by DPR as a regulatory value for establishing buffer zones to protect residents from adverse effects of methyl bromide exposure.
4 METHYL BROMIDE RISK CHARA CTERIZA TION IN CALIFORNIA notes that although the effects seen in the adult rats were dose-related and sta- tistically significant, they were slight or equivocal and only observed in aged rats. Nevertheless, the subcommittee agrees with DPR that this is the correct study to use for a chronic exposure RfC. DPR concluded that 3 ppm was a NOAE1E in two rat reproductive toxicity studies, although the subcommittee questions whether the reduction in fertility observed in the F1 generation was of reproductive origin or developmental origin. Studies conducted in rats and rabbits indicate that in utero exposure to methyl bromide results in developmental toxicity. in rats this was manifested by reduced body and brain weights in pups and reduced fertility in gesta- tionally exposed offspring. In rabbit offspring, gallbladder agenesis, reduced fetal weights, and increased frequency of fused sternebrae were seen. Al- though the subcommittee recognizes that any of those effects individually might be considered equivocal, together they suggest that methyl bromide has the potential to be a developmental toxicant. Recommendations · Studies should be conducted to confirm the neurotoxic effects seen in dogs following subchronic exposures. The developmental and reproductive effects of methyl bromide should be further investigated to determine whether it is a direct-acting repro- ductive toxicant or a developmental toxicant to the reproductive system, whether methyl bromide is excreted in breast milk, and whether the gall- bladder agenesis seen in offspring occurs following a single exposure during a critical period of development. Neurological testing of workers should be conducted to determine possi- ble long-term or permanent effects following occupational exposure to methyl bromide. · DPR should review the literature on methyl bromide and other methylat- ing agents to assist them in understanding why methyl bromide, an in vitro mutagen, is not an in vivo carcinogen. This might also help eluci- date the mechanism of methyl bromide toxicity. Exposure The DPR report presents a substantial amount of data on exposure esti- mates for a wide variety of worker and residential exposure scenarios. The majority of the exposure information is obtained from studies that were con-
EXECUTIVE SUMMARY ~ ducted to establish permit conditions. This information was not always col- lected in a consistent and comprehensive manner, or in compliance with Good Laboratory Practices. The DPR report addresses (1~ exposures of workers, (2) exposures of indi- viduals due to environmental transport of methyl bromide away from the site of direct application, and (3) exposures of residents returning to fumigated houses. DPR focuses principally on occupational exposure scenarios, present- ing data on 160 exposure categories, with estimates for acute (daily), short- term (7 days), seasonal (90 days), and chronic (annual) exposures. The occu- pational exposures range widely from a high of 8,458 ppb to a Tow of 0.6 ppb. DPR provides data from two studies on exposures of residents of houses neighboring fumigated structures. No air sampling was conducted to assess individual exposures near commodity fumigation sites; DPR assumes that people are exposed to concentrations of 2 ~ 0 ppb. Exposure data on residents returning to fumigated homes are taken from five houses in southern CaTifor- nia. Exposure modeling and field studies indicate that some worker exposures exceed protective levels by more than an order of magnitude, whereas poten- tial exposures of residents living near fumigated fields and facilities are un- quantif~ed. Although DPR compiled a large quantity of exposure data in its document, the subcommittee concludes that the exposure analysis is lacking in several respects. The DPR report fails to address several exposure scenarios, includ- ing exposures of residents living near fumigated fields and increased expo- sures of residents and workers resulting from methyl bromide treatment of several agricultural fields simultaneously or consecutively. In addition, the subcommittee concludes that there is considerable uncertainty concerning the analytical recovery methods used in the exposure assessment studies. Much of the data presented by DPR is based on single measurements, and no discus- sion of variability or uncertainty in the measurements is provided. The DPR report also fails to discuss the representativeness of the measurements to the actual exposures experienced by worker or residential populations. DPR makes numerous assumptions regarding durations and levels of exposures, which the subcommittee believes are not explained in sufficient detail to es- tablish whether the assumptions are valid. Recommendations · Further data collection and analysis are necessary to accurately assess worker and residential exposures to methyl bromide. · Improvement is needed in the collection of field data used by DPR to
6 METHYL BROMIDE RISK CHARD CTERIZA TION IN CALIFORNIA assess worker exposure, particularly with regard to the analytical meth- ods used to detect methyl bromide in ambient air and atmospheric condi- tions during sampling. · Further work is needed to determine the best recovery method for meth- yl bromide and how field conditions affect the recovery of methyl bro- mide from air samples. · Air sampling should be conducted for residents living near fumigated fields; these nonoccupational exposures are unquantified at present. · DPR should reevaluate all existing exposure data for variability and un- certainty. Risk Characterization DPR characterized the risks associated with exposure to methyl bromide by using a margin-of-exposure (MOE) approach. DPR compared the human equivalent NOAEL determined from the available animal toxicity data with the anticipated or measured exposures of agricultural workers and residents located near fumigated fields and those entering fumigated homes. The sub- committee found the MOE approach to be generally acceptable for determin- ing which workers and residents are likely to be exposed to potentially harm- fu! concentrations of methyl bromide. However, the subcommittee believes that DPR did not conduct a complete risk assessment, because there was no quantification of the populations of workers that are likely to be exposed or the number of residents living near fields or entering houses. The subcommittee found DPR's use of an MOE to be helpful for estimating risks to some populations, particularly workers. However, the subcommittee has concerns about DPR's use of these MOEs for protecting nonworkers, par- ticularly people living near fumigated fields. The DPR document does not indicate how the MOEs are to be used to determine the protectiveness of the buffer zones specified in the application permits. The document also fails to characterize certain potentially sensitive populations, such as children in schools or living near fumigated fields, although the proposed regulations ad- dress the exposure of children by restricting the application times near schools. The subcommittee concludes that the uncertainties addressed by DPR in the report, including extrapolating from LOAELs to NOAELs and from animals to humans, although important, are only part of the uncertainties that need to be addressed in the risk characterization document. The subcom- mittee finds that DPR's use of a factor of 10 to account for intraspecies varia- tion and a factor of ~ 0 for differences in animal and human toxicity, as well as
EXECUTIVE SUMMARY 7 its use of a benchmark MOE of 100, is consistent with generally accepted risk management practices. The subcommittee concluded that an additional safety factor for infants and children was not necessary, because the NOAELs were adequately conservative. Recommendations · DPR should quantify the number and distribution of workers and resi- dents potentially exposed to methyl bromide. · Buffer zones should be derived based on reasonable worst-case exposure scenarios. · DPR should be more explicit in linking its MOE analysis to the develop- ment of regulatory levels and should indicate how its regulatory goals will be met by its risk characterization.
