Limitations to Empirical Extrapolation Studies: the Case of Bmd Ratios Limitations to Empirical Extrapolation Studies: the Case of Bmd Ratios By

Extrapolation relationships are of keen interest to chemical risk assessment in which they play a prominent role in translating experimentally derived (usually in animals) toxicity estimates into estimates more relevant to human populations. A standard approach for characterizing each extrapolation relies on ratios of pre-existing toxicity estimates. Applications of this "ratio approach" have overlooked several sources of error. This article examines the case of ratios of benchmark doses, trying to better understand their informativeness. The approach involves mathematically modeling the process by which the ratios are generated in practice. Both closed form and simulation-based models of this "data-generating process" (DGP) are developed, paying special attention to the influence of experimental design. The results show the potential for significant limits to informativeness, and revealing dependencies. Future applications of the ratio approach should take imprecision and bias into account. Bootstrap techniques are recommended for gauging imprecision, but more complicated techniques will be required for gauging bias (and capturing dependencies). Strategies for mitigating the errors are suggested.

[1]  R J Kavlock,et al.  Benchmark Dose Workshop: criteria for use of a benchmark dose to estimate a reference dose. , 1995, Regulatory toxicology and pharmacology : RTP.

[2]  M. Pike,et al.  Some tautologous aspects of the comparison of carcinogenic potency in rats and mice. , 1985, Fundamental and applied toxicology : official journal of the Society of Toxicology.

[3]  G. Oehlert A note on the delta method , 1992 .

[4]  S. Crawford,et al.  Analysis of Quantal Response Data , 1994 .

[5]  E Crouch,et al.  On the relationship between carcinogenicity and acute toxicity. , 1989, Risk analysis : an official publication of the Society for Risk Analysis.

[6]  V J Feron,et al.  Sub‐acute versus sub‐chronic oral toxicity study in rats: Comparative study of 82 compounds , 1984, Journal of applied toxicology : JAT.

[7]  R. Griesemer Dose selection for animal carcinogenicity studies: a practitioner's perspective. , 1992, Chemical research in toxicology.

[8]  J. Haseman,et al.  Statistical issues in the design, analysis and interpretation of animal carcinogenicity studies. , 1984, Environmental health perspectives.

[9]  D W Gaylor,et al.  The use of safety factors for controlling risk. , 1983, Journal of toxicology and environmental health.

[10]  E. M. Carter,et al.  Shrinkage Estimators of Relative Potency , 1993 .

[11]  Rosedith Sitgreaves Bowker Statistics, Second Edition , 1983 .

[12]  J I Goodman,et al.  Principles underlying dose selection for, and extrapolation from, the carcinogen bioassay: dose influences mechanism. , 1995, Regulatory toxicology and pharmacology : RTP.

[13]  D. L. McLeish,et al.  Sequential Designs in Bioassay , 1990 .

[14]  N. Reid,et al.  Likelihood , 1993 .

[15]  C. Cox,et al.  An Elementary Introduction to Maximum Likelihood Estimation for Multinomial Models: Birch's Theorem and the Delta Method , 1984 .

[16]  James H. Lambert,et al.  Workshop Overview , 2021, 2021 IEEE VIS Arts Program (VISAP).

[17]  E J Freireich,et al.  Quantitative comparison of toxicity of anticancer agents in mouse, rat, hamster, dog, monkey, and man. , 1966, Cancer chemotherapy reports.

[18]  Sandra J. S. Baird,et al.  Noncancer Risk Assessment: A Probabilistic Alternative to Current Practice , 1996 .

[19]  J. Evans,et al.  Estimating Noncancer Uncertainty Factors: Are Ratios NOAELs Informative? , 1999, Risk analysis : an official publication of the Society for Risk Analysis.

[20]  W. Slob,et al.  A Probabilistic Approach for Deriving Acceptable Human Intake Limits and Human Health Risks from Toxicological Studies: General Framework , 1998 .

[21]  W Slob,et al.  Conversion factors estimating indicative chronic no-observed-adverse-effect levels from short-term toxicity data. , 1996, Regulatory toxicology and pharmacology : RTP.

[22]  Richard Wilson,et al.  Use of Acute Toxicity to Estimate Carcinogenic Risk , 1984 .

[23]  M J Small,et al.  Deriving allowable daily intakes for systemic toxicants lacking chronic toxicity data. , 1987, Regulatory toxicology and pharmacology : RTP.

[24]  R. Hertzberg,et al.  A new method for determining allowable daily intakes. , 1986, Fundamental and applied toxicology : official journal of the Society of Toxicology.

[25]  Prediction of carcinogenic potency from toxicological data. , 1990, Mutation research.

[26]  C. Cox Fieller's theorem, the likelihood and the delta method , 1990 .

[27]  D. Freedman,et al.  How tautological are interspecies correlations of carcinogenic potencies? , 1993, Risk analysis : an official publication of the Society for Risk Analysis.

[28]  Estimation of the weibull shape parameter in small-sample bioassay , 1989 .

[29]  J. Selkirk,et al.  An overview of prechronic and chronic toxicity/carcinogenicity experimental study designs and criteria used by the National Toxicology Program. , 1990, Environmental health perspectives.

[30]  D Krewski,et al.  Determining "safe" levels of exposure: safety factors or mathematical models? , 1984, Fundamental and applied toxicology : official journal of the Society of Toxicology.

[31]  W Leisenring,et al.  Statistical properties of the NOAEL. , 1992, Regulatory toxicology and pharmacology : RTP.

[32]  J. Evans,et al.  Estimating Noncancer Uncertainty Factors: Are Ratios NOAELs Informative? , 1999, Risk analysis : an official publication of the Society for Risk Analysis.

[33]  C C Travis,et al.  Quantitative correlation of carcinogenic potency with four different classes of short-term test data. , 1991, Mutagenesis.

[34]  W Slob,et al.  Assessment factors for human health risk assessment: a discussion paper. , 1999, Critical reviews in toxicology.

[35]  Innovative designs and practices for acute systemic toxicity studies. , 1984, Drug and chemical toxicology.

[36]  J. R. Koehler,et al.  Modern Applied Statistics with S-Plus. , 1996 .

[37]  A. Whitehead,et al.  Statistical evaluation of the fixed-dose procedure. , 1992, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[38]  E Crouch,et al.  Tautology or not tautology? , 1987, Journal of toxicology and environmental health.

[39]  Elaine M. Faustman,et al.  Dose-response assessment for developmental toxicity , 1994 .

[40]  M. Srivastava Multivariate bioassay, combination of bioassays, and Fieller's theorem. , 1986, Biometrics.

[41]  C. Kimmel,et al.  Dose-response assessment for developmental toxicity. II. Comparison of generic benchmark dose estimates with no observed adverse effect levels. , 1994, Fundamental and applied toxicology : official journal of the Society of Toxicology.

[42]  J. O. Irwin,et al.  Statistical Method in Biological Assay , 1953, Nature.

[43]  C C Travis,et al.  Interspecific scaling of toxicity data. , 1988, Risk analysis : an official publication of the Society for Risk Analysis.

[44]  J. Berkson Maximum Likelihood and Minimum x 2 Estimates of the Logistic Function , 1955 .

[45]  J K Haseman,et al.  Issues in carcinogenicity testing: dose selection. , 1985, Fundamental and applied toxicology : official journal of the Society of Toxicology.

[46]  D Krewski,et al.  An overview of the report: correlation between carcinogenic potency and the maximum tolerated dose: implications for risk assessment. , 1993, Risk analysis : an official publication of the Society for Risk Analysis.

[47]  J. Bucher,et al.  Workshop overview. National Toxicology Program Studies: principles of dose selection and applications to mechanistic based risk assessment. , 1996, Fundamental and applied toxicology : official journal of the Society of Toxicology.