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M L Dourson

Publications and source records attributed to M L Dourson.

15 recordsLinked to original sources
PubMed1995

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.

Environmental Health↗
PubMed1992

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.

Animals↗
PubMed1990

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).

Animals↗
PubMed1990

The U.S. Environmental Protection Agency's inhalation RfD methodology: risk assessment for air toxics.

The U.S. Environmental Protection Agency (U.S. EPA) has advocated the establishment of general and scientific guidelines for the evaluation of toxicological data and their use in deriving benchmark values to protect exposed populations from adverse health effects. The Agency's reference dose (RfD) methodology for deriving benchmark values for noncancer toxicity originally addressed risk assessment of oral exposures. This paper presents a brief background on the development of the inhalation reference dose (RfDi) methodology, including concepts and issues related to addressing the dynamics of the respiratory system as the portal of entry. Different dosimetric adjustments are described that were incorporated into the methodology to account for the nature of the inhaled agent (particle or gas) and the site of the observed toxic effects (respiratory or extrarespiratory). Impacts of these adjustments on the extrapolation of toxicity data of inhaled agents for human health risk assessment and future research directions are also discussed.

Administration, Inhalation↗
PubMed1989

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.

Aerosols↗
PubMed1989

Risk assessment initiatives for noncancer endpoints: implications for risk characterization of chemical mixtures.

Current methods employed in risk assessment for noncarcinogens are associated with the estimation of reference doses (RfDs). These strategies reflect (appropriately) a protective philosophy in both theory and practice. The approaches are limited, however, in terms of the ability to project the likelihood of specific hazard above the reference dose and to integrate the health hazards of exposure to chemical mixtures (including both cancer and noncancer endpoints). Ongoing efforts that address guidelines for risk assessment of non-carcinogens, both singly and as components of mixtures, are presented. Included is a description of the range of potential biological response categories and associated parallel issues of adversity and severity. For example, the progression of histopathological change, organ system dysfunction and organismal disability is examined as it may affect risk characterization of mixtures. Mechanistic principles are suggested as an appropriate focus to systematically evaluate this progression. Once established, these principles may provide a reasonable framework in which to more accurately characterize risks associated with chemical mixtures.

Dose-Response Relationship, Drug↗
PubMed1985

Novel methods for the estimation of acceptable daily intake.

This paper describes two general methods for estimating ADIs that circumvent some of the limitations inherent in current approaches. The first method is based on a graphic presentation of toxicity data and is also shown to be useful for estimating acceptable intakes for durations of toxicant exposure other than the entire lifetime. The second method uses dose-response or dose-effect data to calculate lower CLs on the dose rate associated with specified response or effect levels. These approaches should lead to firmer, better established ADIs through increased use of the entire spectrum of toxicity data.

Animals↗
PubMed1983

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.

Animals↗
PubMed1983

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.

Animals↗
PubMed1982

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.

Adenoma↗
PubMed1982

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.

Adenoma↗
PubMed1981

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.

Adenoma↗
PubMed1977

Effects of cytosine arabinoside on in vivo and in vitro mouse limb development.

When pregnant mice were exposed to 40 mg per kg of cytosine arabinoside (ara-C) on days 10 to 12 of gestation, adactylous limbs with large, distally located blisters were found when the fetuses were examined on day 18. Embryonic limbs exposed transplacentally under identical conditions and explanted to culture exhibited the same morphological abnormality as did limbs exposed directly in culture to 0.1 to 1 microgram per ml of ara-C. Two noncytotoxic analogues of ara-C, uridine arabinoside (ara-U) and hypoxanthine arabinose (ara-HX), had no influence on morphological differentiation of limbs in vitro. Ara-C alone caused a dose-related decrease in uptake of 3H-thymidine and 35SO4 in cultured limb buds. Production of this morphologically distinct malformation in vitro will allow detailed biochemical investigations on the effect of ara-C limb ectodermal-mesenchymal interactions.

Abnormalities, Drug-Induced↗
PubMedDate not supplied

On reference dose (RfD) and its underlying toxicity data base.

The toxicity data of pesticides were summarized and compared amongst different animal species and types of bioassays. These comparisons showed the expected inter-species and inter-bioassay variability. After quantitative and statistical analysis of these data, it was concluded that, on the average, a 2-year dog bioassay detected toxic responses at similar doses as a 2-year rat study, and that both of these bioassays detected toxic responses at lower doses than either a rat 2-generation bioassay, a rat developmental toxicity study, or a 2-year mouse bioassay. Although these chronic dog and rat bioassays were found to detect toxic responses at lower doses than the other studies listed, this analysis does not reflect the seriousness of the effects that were compared. Within the confines of this analysis, then, it appears that a 2-year dog and rat study, reproductive and developmental bioassays are a sufficient data base on which to estimate high confidence Reference Doses (RfDs), and furthermore, that an additional uncertainty factor is needed to estimate RfDs to account for this inter-species and inter-bioassay variability when fewer than this number of bioassays are available.

Animals↗