Technical Recommendations for Department of Pesticide Regulation Risk Assessments
This appendix highlights specific technical observations made by the committee in its review of the Department of Pesticide Regulation (DPR) risk-assessment guidance and the risk-characterization documents on carbaryl, chloropicrin, and methyl iodide. These observations led to the conceptual recommendations made in the body of this report. The committee here offers recommendations on specific aspects of the performance of DPR’s risk assessments.
DEFINITION OF ADVERSE EFFECTS
Sound scientific practice for hazard identification involves a determination of whether an observed effect is adverse. The US Environmental Protection Agency (EPA) defines an adverse effect as “a biochemical change, functional impairment, or pathologic lesion that affects the performance of the whole organism, or that reduces an organism’s ability to respond to an additional environmental challenge” (EPA 2014a). Defining adverse effects is acknowledged to be difficult (e.g., see Lewis et al. 2002): not all effects are adverse, some effects might be adaptive responses, and others are precursors to adverse effects. Defining adverse effects is important as regulatory agencies begin to incorporate suggestions from the National Research Council Report Toxicity Testing in the 21st Century: A Vision and a Strategy (NRC 2007) into risk assessments in that precursor effects determined in in vitro studies may be suitable end points for risk assessments.
DPR’s risk-characterization documents refer to no-observed-adverse-effect levels (NOAELs) and no-observed-effect levels (NOELs), both of which seem to be considered relevant to hazard identification. However, it is unclear how DPR defines an adverse effect on which those levels are based. The committee recommends that DPR clarify its definition and the criteria that it uses to make determinations. Consideration should be given to the technical support document developed by the Office of Environmental Health Hazard Assessment (OEHHA) for deriving noncancer reference exposure levels (OEHHA 2008) and to the work of EPA (2002) and the European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC 2002; Lewis et al. 2002). Consideration should also be given to establishing guidance or using existing guidance (e.g., ATSDR 2007; OEHHA 2008) on categorizing effects as mild, moderate, or severe.
ROUTE-TO-ROUTE EXTRAPOLATION
Extrapolation of dose–response data from one route of exposure to another is accompanied by uncertainty, which should be minimized as much as the data and methods allow. The major factors contributing to the uncertainty are the relevance of portal-of-entry effects in the lung or gastrointestinal tract to the extrapolated route of exposure, the liver first-pass effects that follow oral dosing that would result in an expectation of adverse effects different from those due to inhalation exposure, and the accuracy of dosimetry adjustments to normalize the internal dose and
biologically effective dose achieved by the compared exposure routes (pharmacokinetic differences). If either a first-pass effect or portal-of-entry effect is present, route-to-route extrapolation is not recommended by EPA for derivation of health values (EPA 1994). Typically, EPA does not perform such extrapolations for fumigant risk assessments when adequate inhalation data are available but prefers to use an inhalation-specific approach that estimates a human-equivalent concentration.
Route-to-route extrapolation may be performed when a chemical’s mode of action has been characterized, the relevant dose metric has been identified (for example, parent chemical or metabolite), and a physiologically based pharmacokinetic (PBPK) model or an optimal inhalation model is available. If such models are not available, route-to-route extrapolation should be performed only when defensible (as discussed above). The committee recommends that DPR acknowledge the uncertainty and provide guidance on when a route-to-route extrapolation is defensible. A pertinent resource is OEHHA’s draft update of risk-assessment guidelines for its Air Toxics Hot Spots Program (OEHHA 2014). If applicable to DPR’s risk-assessment practices, relevant guidance could be adopted and would help to promote consistency between the groups.
In its review of DPR’s risk-characterization documents on fumigants, the committee noted that DPR estimates doses of active ingredients (AIs) from inhalation studies by using a body-burden approach, and it was unclear why such estimation was necessary. For example, in the carcinogenic assessment of chloropicrin (DPR 2012), an inhalation study of mice that developed lung adenomas and carcinomas (portal-of-entry effects) after chronic exposure to chloropicrin was available. DPR adjusted the air concentrations (in parts per million) from that study into doses (milligrams per kilogram per day) and then converted the doses to human equivalents by multiplying by an interspecies scaling factor applicable for an oral route of exposure (body weight to the ¾ power). The resulting dose was converted back to an air concentration. Because chloropicrin has an adequate inhalation study in mice and produces portal-of-entry effects, route-to-route extrapolation is unnecessary. DPR should have used inhalation-specific dosimetric adjustments. Guidance on performing such adjustments is available, as is guidance on when route-to-route extrapolation is scientifically defensible (see EPA 1994).
BENCHMARK-DOSE MODELING
DPR uses benchmark-dose (BMD) modeling in its dose–response assessments of AIs when only a lowest-observed-adverse-effect level has been identified in a study (DPR 2004a,b). The committee supports BMD modeling and recommends that DPR expand its use of it to all cases in which the dose–response data are amenable to modeling, even when a NOEL or NOAEL has been identified. EPA has more recent guidance on BMD modeling (EPA 2012a), which DPR should review and use to update its BMD guidance documents, if needed, to reflect the latest scientific recommendations. The committee observed that the response level chosen for the BMD and BMDL varies from case to case. For example, 1%, 2.5%, 5%, and 10% response levels were used for chloropicrin (DPR 2012). That can lead to inconsistency in end-point comparisons between different critical effects. In addition, caution should be used in extrapolating far below the observed range of data because it introduces uncertainty into the assessment. Expanding the use of BMD methods and defining response levels consistently will allow DPR to be consistent with dose–response practices of OEHHA (2008) and EPA (2012a).
CHEMICAL-SPECIFIC ADJUSTMENT FACTORS
The committee recommends that DPR consider the derivation of chemical-specific adjustment factors if chemical-specific data are available. The International Programme on Chemical Safety has guidance on the data needed to develop chemical-specific adjustment factors to account for interspecies differences and human variability in toxicokinetics and toxicodynamics
(IPCS 2001, 2005). EPA (2014b) guidance on data-derived extrapolation factors provides a fairly similar approach.
ANIMAL-TO-HUMAN DOSIMETRIC ADJUSTMENTS
Animal-to-human dosimetric adjustments may be performed when a chemical’s mode of action has been characterized, the relevant dose metric has been identified (for example, parent chemical or metabolite), and a PBPK model or an optimal inhalation model is available. If models are not available, default procedures are typically used. DPR and EPA appear to differ in how they perform default animal-to-human dosimetric adjustments. For example, DPR (2011) adjustments appear to be based on different breathing rates for different life stages to estimate inhalation risk to humans whereas EPA’s calculations depend on default animal-to-human dosimetric adjustments (EPA 1994). DPR does not use EPA’s default adjustments for extrarespiratory effects (systemic effects), because of the uncertainty associated with the lack of chemical-specific data on human and animal blood-gas ratios (DPR 2011). The committee recommends that DPR review EPA (2012b) recommendations for animal-to-human dosimetric adjustments for adverse respiratory effects in the extrathoracic, tracheobronchial, and pulmonary regions for gases and vapors. The dosimetric adjustments are default procedures and are considered appropriate on the basis of PBPK inhalation modeling and measured data for various chemicals. EPA also judges that the adjustments are protective of children in the great majority of cases. Specific exceptions are discussed (see EPA 2012b).
Attachment 1 of DPR (2011) focused on inhaled gases and did not address dosimetric adjustment factors for inhaled particles or aerosols. For inhaled particles and aerosols, the committee recommends that DPR consider EPA (1994) procedures to determine the appropriate dosimetric adjustment factor except for rat inhalation studies. For rats, the multiple-path particle dosimetry model, version 2, for performing dosimetric adjustments (CIIT 2004) is generally used.
The committee notes that DPR sometimes uses PBPK models to conduct animal-to-human dosimetric adjustments. Other types of optimal inhalation-dosimetry models that DPR could use are available. Hanna et al. (2001) describe differences between basic inhalation-dosimetry models and provide some guidance on factors to consider in choosing model structures.
DEFAULT ANIMAL-TO-HUMAN DOSIMETRIC ADJUSTMENTS THAT AFFECT THE VALUE OF THE INTERSPECIES UNCERTAINTY FACTOR
The DPR (2011) guidance document for default uncertainty factors acknowledges some inconsistency in how interspecies extrapolations are performed by DPR, OEHHA, and EPA. All groups consider that the interspecies uncertainty factor consists of a toxicokinetic portion (100.5) and a toxicodynamic portion (100.5). EPA (1994) reference-concentration methods recommend that for the inhalation route of exposure, when the animal concentration can be adjusted by a dosimetric adjustment factor (if data are available) to a human-equivalent concentration, the pharmacokinetic portion (100.5) be reduced to 1 because toxicokinetic differences between animals and humans have been taken into consideration. OEHHA (2008) recommends that when such an adjustment is performed, the toxicokinetic portion of the uncertainty factor be reduced to 2, rather than 1, to reflect remaining uncertainty about toxicokinetics due to metabolism and excretion. DPR’s guidance does not appear to allow estimation of a human-equivalent concentration and presents default values of 100.5 for both the pharmacokinetic and pharmacodynamic portions of the uncertainty factor. The committee recommends that DPR’s guidance be updated to allow estimation of human-equivalent concentrations from animal data and relevant adjustment of the pharmacokinetic portion of the uncertainty factor applied for interspecies differences.
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