Critical issues in benchmark calculations from continuous data.

The benchmark dose (BMD) is a dose that causes a specified low level of additional risk and is estimated using a statistical dose-response analysis. Regulatory agencies are using a statistical lower bound on the BMD in the place of the NOAEL for establishing exposure limits. However, there are still several issues regarding the BMD for which no clear consensus has emerged, particularly with respect to calculation of BMD from continuous response data. These include: (1) how to define the BMD from continuous data so that they are comparable to BMD derived from binary data, (2) what dose-response models and levels of additional risk should be used to calculate the BMD. The "hybrid" approach (Gaylor and Slikker, 1990; Crump, 1995) expresses the BMD from continuous data in terms that are directly comparable to those obtained using binary data. Several features of the hybrid approach are examined, with the emphasis on application to epidemiological data. The effect on the BMD of converting continuous data to binary form is quantified. Model uncertainty is explored, and the need for controlling this uncertainty by restricting the class of allowable models is demonstrated. Control data, which are often not available in epidemiological studies, are shown to have a limited effect upon the BMD so long as the model for the mean response is linear or convex. Such models are also biologically plausible, at least at low doses. Based on these and other considerations, suggestions are made for selecting a model for applying the hybrid approach and for selecting the level of additional risk on which to base the BMD.

[1]  S. Moolgavkar,et al.  A Method for Computing Profile-Likelihood- Based Confidence Intervals , 1988 .

[2]  Kenny S. Crump,et al.  Calculation of Benchmark Doses from Continuous Data , 1995 .

[3]  Abraham Silvers,et al.  Influence of Prenatal Mercury Exposure Upon Scholastic and Psychological Test Performance: Benchmark Analysis of a New Zealand Cohort , 1998, Risk analysis : an official publication of the Society for Risk Analysis.

[4]  C J Portier,et al.  Characterizing Dose‐Response I: Critical Assessment of the Benchmark Dose Concept , 1998, Risk analysis : an official publication of the Society for Risk Analysis.

[5]  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.

[6]  D. Gaylor Quantalization of continuous data for benchmark dose estimation. , 1996, Regulatory toxicology and pharmacology : RTP.

[7]  Ralph L. Kodell,et al.  Statistical methods of risk assessment for continuous variables , 1993 .

[8]  C Cox,et al.  Benchmark concentrations for methylmercury obtained from the Seychelles Child Development Study. , 2000, Environmental health perspectives.

[9]  Roberta F. White,et al.  Cognitive deficit in 7-year-old children with prenatal exposure to methylmercury. , 1997, Neurotoxicology and teratology.

[10]  D G Hoel,et al.  Fundamental carcinogenic processes and their implications for low dose risk assessment. , 1976, Cancer research.

[11]  N Keiding,et al.  Benchmark Dose Calculation from Epidemiological Data , 2001, Biometrics.

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

[13]  K. Victorin,et al.  Application of the benchmark method to risk assessment of trichloroethene. , 1995, Regulatory toxicology and pharmacology : RTP.

[14]  H. Clewell,et al.  Reanalysis of dose-response data from the Iraqi methylmercury poisoning episode. , 1995, Risk analysis : an official publication of the Society for Risk Analysis.

[15]  S. T. Buckland,et al.  An Introduction to the Bootstrap. , 1994 .

[16]  R L Kodell,et al.  Upper confidence limits on excess risk for quantitative responses. , 1993, Risk analysis : an official publication of the Society for Risk Analysis.

[17]  W Slikker,et al.  Risk assessment for neurotoxic effects. , 1990, Neurotoxicology.

[18]  K S Crump,et al.  A new method for determining allowable daily intakes. , 1984, Fundamental and applied toxicology : official journal of the Society of Toxicology.