The Scientific Basis of Uncertainty Factors Used in Setting Occupational Exposure Limits.

The uncertainty factor concept is integrated into health risk assessments for all aspects of public health practice, including by most organizations that derive occupational exposure limits. The use of uncertainty factors is predicated on the assumption that a sufficient reduction in exposure from those at the boundary for the onset of adverse effects will yield a safe exposure level for at least the great majority of the exposed population, including vulnerable subgroups. There are differences in the application of the uncertainty factor approach among groups that conduct occupational assessments; however, there are common areas of uncertainty which are considered by all or nearly all occupational exposure limit-setting organizations. Five key uncertainties that are often examined include interspecies variability in response when extrapolating from animal studies to humans, response variability in humans, uncertainty in estimating a no-effect level from a dose where effects were observed, extrapolation from shorter duration studies to a full life-time exposure, and other insufficiencies in the overall health effects database indicating that the most sensitive adverse effect may not have been evaluated. In addition, a modifying factor is used by some organizations to account for other remaining uncertainties-typically related to exposure scenarios or accounting for the interplay among the five areas noted above. Consideration of uncertainties in occupational exposure limit derivation is a systematic process whereby the factors applied are not arbitrary, although they are mathematically imprecise. As the scientific basis for uncertainty factor application has improved, default uncertainty factors are now used only in the absence of chemical-specific data, and the trend is to replace them with chemical-specific adjustment factors whenever possible. The increased application of scientific data in the development of uncertainty factors for individual chemicals also has the benefit of increasing the transparency of occupational exposure limit derivation. Improved characterization of the scientific basis for uncertainty factors has led to increasing rigor and transparency in their application as part of the overall occupational exposure limit derivation process.

Human health risks from mercury exposure from broken compact fluorescent lamps (CFLs).

Human health risk to infants/toddlers and adults was evaluated based on two exposure scenarios from compact fluorescent lamp (CFL) breakage; first in a room with no ventilation and no clean-up, and second in a room with adequate ventilation and clean-up. Concentration data from multiple exposure scenarios tested in a study by Stahler et al. (2008) were compared to human toxicity benchmarks to calculate hazard quotients. For the no clean-up scenario, hazard quotients were generally less than 1, suggesting an unlikely health risk. When the room was ventilated and the broken CFL was cleaned-up, mercury concentrations were generally lower. A review of release scenarios, along with duration-adjusted toxicity benchmarks, indicated that few releases produced levels of concern, but some scenarios resulted in exceedance of risk targets and require further study. Uncertainties in this screening characterization include assumptions about room size, ventilation, age of lamp, the distribution of mercury in the room, and also the choice of the toxicity benchmarks used to develop the hazard quotients.

Relationship of lung adenoma prevalence and growth rate to acute urethan dose and target cell number.

Outbred Swiss Cox mice of both sexes were given single ip injections of 0.5--2.0 mg urethan/g body weight. Lung adenomas began to grow about 7 days after urethan administration. The relationship of plateau tumor level to dose was slightly concave upward. However, the relationship of average tumor number per 10(6) surviving target cells or alveolar type II cells to dose was markedly concave upward. Thus the definition of the urethan dose-lung adenoma prevalence curve should take into account the urethan cytotoxicity. Tumor diameters followed a log normal distribution pattern. The rate of change of geometric mean tumor diameter was independent of sex and urethan dose. In another experiment Swiss Cox mice received ip injections of 1.5 mg urethan/g body weight, and 4 weeks later chronic exposure to urethan in the drinking water was begun. The growth rate of adenomas induced by the single urethan injection was unaffected by subsequent chronic-urethan administration. The results support the common assumption that tumor growth rate is independent of the rate of chronic administration of a carcinogen.

Relationship between urethan dose rate and adenoma latency: relevance of tumor growth rate and target cell number.

Outbred Swiss Cox mice of both sexes were chronically exposed to urethan added to their drinking water at levels of 0.02--0.10% by weight. The number and sizes of lung adenomas that developed as a result were monitored as functions of time and dose rate (DR). The relationship between dose per unit time, or DR, and time (t1) needed for the development of a mean of one observable tumor per mouse was: DR x tn1 = k, where K and n are constants. The value of n was 2.75. This value could be largely accounted for by the DR-independent tumor growth time, although an increase in the number of target cells at higher urethan dose rates may also be a factor in the relationship between DR and t1. Examination of the relationships between cumulative incidence and DR and between cumulative incidence and adenoma induction time suggests that urethan acts at one stage of a two-stage mechanism in the induction of mouse lung adenomas.

The current use of studies on promoters and cocarcinogens in quantitative risk assessment.

Several of the priority pollutants discussed in EPA's Ambient Water Quality Criteria documents have been reported to have promotion or cocarcinogenic activity. For example, phenol appears to have tumor-promoting activity in mice when repeatedly applied after initiation with either 7,12-dimethyl-1,2-benzanthracene (DMBA) or benzo(a)pyrene (BaP). Similarly, it has been reported that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a potent promoter of liver tumors as well as a cocarcinogen. However, in developing guidelines to derive ambient water quality criteria, it became apparent that satisfactory approaches had not been developed for using promotion/cocarcinogen data in human health risk estimation, nor were available promotion and/or cocarcinogen data on individual chemicals strong enough to permit a defensible quantitative risk estimation, if such approaches had existed. For this reason, the criteria derived for pollutants with reported promotion/cocarcinogenic activities were based on approaches for carcinogenic (e.g., TCDD), toxic (e.g., fluoranthene) or organoleptic effects (e.g., 2,4-dichlorophenol). Nonetheless, with advances in studies on both the biological mechanisms and dose/response patterns of promoters and cocarcinogens, it may be possible to develop a scientifically valid quantitative approach to use this type of data for derivation of ambient water quality criteria or other risk assessments. Some progress toward this goal and the problems associated with this effort are discussed.

Applications of mechanistic data in risk assessment: the past, present, and future.

Mechanistic data, when available, have long been considered in risk assessment, such as in the development of the nitrate RfD based on effects in a sensitive group (infants). Recent advances in biology and risk assessment methods have led to a tremendous increase in the use of mechanistic data in risk assessment. Toxicokinetic data can improve extrapolation from animals to humans and characterization of human variability. This is done by the development of improved tissue dosimetry, by the use of uncertainty factors based on chemical-specific data, and in the development of physiologically based pharmacokinetic (PBPK) models. The development of the boron RfD illustrates the use of chemical-specific data in the improved choice of uncertainty factors. The draft cancer guidelines of the U.S. Environmental Protection Agency emphasize the use of mode of action data. The first choice under the guidelines is to use a chemical-specific, biologically based dose-response (BBDR) model. In the absence of a BBDR model, mode of action data are used to determine whether low-dose extrapolation is done using a linear or nonlinear (margin of exposure) approach. Considerations involved in evaluating a hypothesized mode of action are illustrated using 1,3-dichloropropene, and use of a BBDR model is illustrated using formaldehyde. Recent developments in molecular biology, including transgenic animals, microarrays, and the characterization of genetic polymorphisms, have significant potential for improving risk assessments, although further methods development is needed. Overall, use of mechanistic data has significant potential for reducing the uncertainty in assessments, while at the same time highlighting the areas of uncertainty.

Reduced prevalence and growth rate of urethane-induced lung adenomas in ageing adult strain A mice.

Following administration of 1.0 mg of urethane/g body wt the average diameter and prevalence of lung adenomas in adult strain. A mice were found to be progressively smaller in animals of progressively greater age at initiation of treatment. Reduction of tumor diameters below detectibility in animals in the older treatment groups could not account for the concurrent reduction in prevalence. Explanations for the observed data in ageing animals based on considerations of reduced immunocompetence or on decreased urethane metabolism or distribution were also considered insufficient. Possible mechanisms for the observed data are discussed.

Guidelines for application of chemical-specific adjustment factors in dose/concentration-response assessment.

This manuscript addresses guidance in the use of kinetic and dynamic data to inform quantitatively extrapolations for interspecies differences and human variability in dose-response assessment developed in a project of the International Programme on Chemical Safety (IPCS) initiative on Harmonisation of Approaches to the Assessment of Risk from Exposure to Chemicals. The guidance has been developed and refined through a series of planning and technical meetings and larger workshops of a broad range of participants from academia, government agencies and the private sector. The guidance for adequacy of data for replacement of common defaults for interspecies differences and human variability is presented in the context of several generic categories including: determination of the active chemical species, choice of the appropriate metric (kinetic components) or endpoint (dynamic components) and nature of experimental data, the latter which includes reference to the relevance of population, route and dose and the adequacy of the number of subjects/samples. The principal objective of this guidance developed primarily as a resource for risk assessors, is to foster better understanding of the components of and criteria for adequacy of chemical-specific data to quantitate interspecies differences and human variability in kinetics and dynamics. It is anticipated that this guidance will also encourage the development of appropriate data and facilitate their incorporation in a consistent fashion in dose-response assessment for regulatory purposes (IPCS, 2001).

Uncertainties in the reference dose for methylmercury.

This paper critically examines the National Academy of Sciences and the National Research Council report on the toxicological effects of methyl mercury and the recently published US Environmental Protection Agency Reference Dose (RfD) for Methylmercury. Particular scrutiny is placed on the choice of the critical study and the underlining assumptions utilized in the selection of specific uncertainty factors (UFs) and the rationale for using a less-than-default factor of 10. The UFs that were utilized or considered by other agencies and organizations are also critically examined, explained and compared to one another. Based on these analyses, the authors suggest research that could be performed that would ameliorate the uncertainty of choosing a more precise partial UFor that may even provide completeness of database to allow for selecting of a UF for unity, thus improving the precision of the current published RfD.

Safety/risk assessment of pesticides: principles, procedures and examples.

The principles and procedures for the assessment of the safety/risk of chemical used by the relevant WHO and EPA expert groups are outlined. The assessment in terms of acceptable daily intakes (ADIs) and reference doses (RfDs) of 25 pesticides is listed. The pesticides assessed are acephate, alachlor, amitrole, azinphos-methyl, benomyl, biphenthrin, bromophos, chlordane, chlorthalonil, cyhalothrin, DDT, EPTC, ethion, folpet, fosetyl-al, glyphosate, isofenphos, methomyl, methyl mercury, paraquat, phosphamidon, systhane, terbutyn, tribultyltin oxide, and vinclozin. In addition, their critical effects, the no-observed-effect levels and the size of the safety/uncertainty factors used are also listed to illustrate the diversity of the toxic effects and the resulting assessments. Furthermore, the enormous amount of data reviewed and the complex scientific judgement involved are also indicated. Considering the various uncertainties existing, the ADIs and RfDs do not differ appreciably in most instances. However, marked differences exist between the ADIs and RfDs of DDT and chlordane. It is suggested that re-evaluation be done on these, and perhaps other, chemicals.

Mathematical modelling and quantitative methods.

The present review reports on the mathematical methods and statistical techniques presently available for hazard characterisation. The state of the art of mathematical modelling and quantitative methods used currently for regulatory decision-making in Europe and additional potential methods for risk assessment of chemicals in food and diet are described. Existing practices of JECFA, FDA, EPA, etc., are examined for their similarities and differences. A framework is established for the development of new and improved quantitative methodologies. Areas for refinement, improvement and increase of efficiency of each method are identified in a gap analysis. Based on this critical evaluation, needs for future research are defined. It is concluded from our work that mathematical modelling of the dose-response relationship would improve the risk assessment process. An adequate characterisation of the dose-response relationship by mathematical modelling clearly requires the use of a sufficient number of dose groups to achieve a range of different response levels. This need not necessarily lead to an increase in the total number of animals in the study if an appropriate design is used. Chemical-specific data relating to the mode or mechanism of action and/or the toxicokinetics of the chemical should be used for dose-response characterisation whenever possible. It is concluded that a single method of hazard characterisation would not be suitable for all kinds of risk assessments, and that a range of different approaches is necessary so that the method used is the most appropriate for the data available and for the risk characterisation issue. Future refinements to dose-response characterisation should incorporate more clearly the extent of uncertainty and variability in the resulting output.

Boron tolerable intake: re-evaluation of toxicokinetics for data-derived uncertainty factors.

Boron, which is ubiquitous in the environment, causes developmental and reproductive effects in experimental animals. This observation has led to efforts to establish a Tolerable Intake value for boron. Although risk assessors agree on the use of fetal weight decreases observed in rats as an appropriate critical effect, consensus on the adequacy of toxicokinetic data as a basis for replacement of default uncertainty factors remains to be reached. A critical analysis of the existing data on boron toxicokinetics was conducted to clarify the appropriateness of replacing default uncertainty factors (10-fold for interspecies differences and 10-fold for intraspecies differences) with data-derived values. The default uncertainty factor for variability in response from animals to humans of 10-fold (default values of 4-fold for kinetics and 2.5-fold for dynamics) was recommended, since clearance of boron is 3- to 4-fold higher in rats than in humans and data on dynamic differences--in order to modify the default value--are unavailable. A data-derived adjustment of 6-fold (1.8 for kinetics and 3.1 for dynamics) rather than the default uncertainty factor of 10-fold was considered appropriate for intrahuman variability, based on variability in glomerular filtration rate during pregnancy in humans and the lack of available data on dynamic differences. Additional studies to investigate the toxicokinetics of boron in rats would be useful to provide a stronger basis for replacement of default uncertainty factors for interspecies variation.

Safety/risk assessment of chemicals compared for different expert groups.

Two sets of 65 risk/safety assessments are compared. These assessments, mostly for pesticide chemicals, were developed by the World Health Organization (WHO) and the U.S. Environmental Protection Agency (EPA) at different times, often with different toxicity data, and with slightly different methods. Despite these differences, 38 sets of assessments give values that are within a 3-fold range of each other, 18 of these 38 are essentially identical (when rounded to one digit of precision), although not always for the same reasons. An additional 20 sets give values that lie within a 30-fold range; 6 sets lie within a 300-fold range; and the bromomethane ADI and RfD are 700-fold apart. In addition, on average the EPA values are lower than the WHO numbers. These comparisons are discussed in relationship to a developing world-wide consensus that the methods for evaluating the safety/risks from various chemicals should be more consistent and the resulting assessments should be more comparable. Moreover, we argue that an established assessment and associated information from one expert group should be routinely discussed in the ongoing evaluation of a chemical by another expert group. A procedure for effecting more consistency among such expert groups is proposed.

Inhalation reference dose (RfDi): an application of interspecies dosimetry modeling for risk assessment of insoluble particles.

Accurate extrapolation of animal toxicity data for human health risk assessment requires determination of the effective dose to the target tissue and the sensitivity of the target tissue to that dose. The methodology for deriving reference doses [the U.S. Environmental Protection Agency's (EPA) benchmark values for gauging systemic toxicity] for oral exposures has not included dosimetry modeling. Dosimetry data facilitate evaluation of concentration-response data with respect to the dose-response relationships used in quantitative risk assessment. Extension of this methodology to derivation of inhalation reference doses (RfDi) should account for the dynamics of the respiratory system as the portal of entry. Predictive physiologically based modeling of the inhalation of reactive gases has recently been demonstrated (Overton and Miller 1988). Models that describe the deposition of hygroscopic particles and account for chemical factors that affect clearance mechanisms and gas uptake are under development. This paper presents a method for calculating a dosimetric adjustment factor based on the values for the initial deposited dose of insoluble particles in an animal species and in humans. The ratio of these two values serves as a scaling factor that can be applied in the R f D methodology to account for the dosimetric differences in the inhaled deposited dose. This application for insoluble particles illustrates the feasibility of interspecies dosimetry calculations for extrapolating the toxicological results of inhaled agents to human exposure conditions for more accurate risk estimation.

Pediatric susceptibility to 18 industrial chemicals: a comparative analysis of newborn with young animals.

We comprehensively re-analyzed the toxicity data for 18 industrial chemicals from repeated oral exposures in newborn and young rats, which were previously published. Two new toxicity endpoints specific to this comparative analysis were identified, the first, the presumed no observed adverse effect level (pNOAEL) was estimated based on results of both main and dose-finding studies, and the second, the presumed unequivocally toxic level (pUETL) was defined as a clear toxic dose giving similar severity in both newborn and young rats. Based on the analyses of both pNOAEL and pUETL ratios between the different ages, newborn rats demonstrated greater susceptibility (at most 8-fold) to nearly two thirds of these 18 chemicals (mostly phenolic substances), and less or nearly equal sensitivity to the other chemicals. Exceptionally one chemical only showed toxicity in newborn rats. In addition, Benchmark Dose Lower Bound (BMDL) estimates were calculated as an alternative endpoint. Most BMDLs were comparable to their corresponding pNOAELs and the overall correlation coefficient was 0.904. We discussed how our results can be incorporated into chemical risk assessment approaches to protect pediatric health from direct oral exposure to chemicals.

Reference dose (RfD): description and use in health risk assessments.

For many years the concept of the "acceptable daily intake" has served the toxicological and regulatory fields quite well. However, as approaches to assessing the health significance of exposures to noncarcinogenic substances receive greater scrutiny, some difficulties with this traditional approach have become more apparent. Consequently, the concept of the "reference dose" is introduced in order to avoid use of prejudicial terms (e.g., "safety" and "acceptable"), to promote greater consistency in the assessment of noncarcinogenic chemicals, and to maintain the functional separation between risk assessment and risk management.

Regulatory history and experimental support of uncertainty (safety) factors.

A synthesis of available literature on uncertainty (safety) factors which are used to estimate acceptable daily intakes (ADIs) for toxicants is presented. This synthesis reveals reasonable qualitative biological premises, as well as specific biological data that support both the use and choice of these factors. A suggestion is made in order to derive a range of ADI. Research needs in various areas of uncertainty are also identified.

Route-to-route extrapolation of the toxic potency of MTBE.

MTBE is a volatile organic compound used as an oxygenating agent in gasoline. Inhalation from fumes while refueling automobiles is the principle route of exposure for humans, and toxicity by this route has been well studied. Oral exposures to MTBE exist as well, primarily due to groundwater contamination from leaking stationary sources, such as underground storage tanks. Assessing the potential public health impacts of oral exposures to MTBE is problematic because drinking water studies do not exist for MTBE, and the few oil-gavage studies from which a risk assessment could be derived are limited. This paper evaluates the suitability of the MTBE database for conducting an inhalation route-to-oral route extrapolation of toxicity. This includes evaluating the similarity of critical effect between these two routes, quantifiable differences in absorption, distribution, metabolism, and excretion, and sufficiency of toxicity data by the inhalation route. We conclude that such an extrapolation is appropriate and have validated the extrapolation by finding comparable toxicity between a subchronic gavage oral bioassay and oral doses we extrapolate from a subchronic inhalation bioassay. Our results are extended to the 2-year inhalation toxicity study by Chun et al. (1992) in which rats were exposed to 0, 400, 3000, or 8000 ppm MTBE for 6 hr/d, 5 d/wk. We have estimated the equivalent oral doses to be 0, 130, 940, or 2700 mg/kg/d. These equivalent doses may be useful in conducting noncancer and cancer risk assessments.

Fish consumption advisories: toward a unified, scientifically credible approach.

A model is proposed for fish consumption advisories based on consensus-derived risk assessment values for common contaminants in fish and the latest risk assessment methods. The model accounts in part for the expected toxicity to mixtures of chemicals, the underlying uncertainties in the health and exposure data, and the amount of contaminated fish consumed. Application of the model to a larger number of chemicals is possible. Noncancer toxicity is used as an example, but this model is applicable for risks from cancer as well. A second related model is proposed that is useful for comparing potential risks among sites (e.g., rivers and lakes).