Evaluation of the Benchmark Dose for Point of Departure Determination for a Variety of Chemical Classes in Applied Regulatory Settings

Authors

  • Hoda Izadi,

    1. New Substances Assessment and Control Bureau, Health Canada, Ottawa, Ontario, Canada.
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  • Jean E. Grundy,

    Corresponding author
    1. New Substances Assessment and Control Bureau, Health Canada, Ottawa, Ontario, Canada.
      Jean E. Grundy, New Chemical Substances 2, Safe Environments Directorate, Health Canada, 4th Fl., Rm. 4-013A, 269 Laurier Ave. W., Mail Stop: 4904A, Ottawa, Ontario KIA 0k9, Canada; jean.grundy@hc-sc.gc.ca.
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  • Ranjan Bose

    1. New Substances Assessment and Control Bureau, Health Canada, Ottawa, Ontario, Canada.
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Jean E. Grundy, New Chemical Substances 2, Safe Environments Directorate, Health Canada, 4th Fl., Rm. 4-013A, 269 Laurier Ave. W., Mail Stop: 4904A, Ottawa, Ontario KIA 0k9, Canada; jean.grundy@hc-sc.gc.ca.

Abstract

Repeated-dose studies received by the New Substances Assessment and Control Bureau (NSACB) of Health Canada are used to provide hazard information toward risk calculation. These studies provide a point of departure (POD), traditionally the NOAEL or LOAEL, which is used to extrapolate the quantity of substance above which adverse effects can be expected in humans. This project explored the use of benchmark dose (BMD) modeling as an alternative to this approach for studies with few dose groups. Continuous data from oral repeated-dose studies for chemicals previously assessed by NSACB were reanalyzed using U.S. EPA benchmark dose software (BMDS) to determine the BMD and BMD 95% lower confidence limit (BMDL05) for each endpoint critical to NOAEL or LOAEL determination for each chemical. Endpoint-specific benchmark dose-response levels , indicative of adversity, were consistently applied. An overall BMD and BMDL05 were calculated for each chemical using the geometric mean. The POD obtained from benchmark analysis was then compared with the traditional toxicity thresholds originally used for risk assessment. The BMD and BMDL05 generally were higher than the NOAEL, but lower than the LOAEL. BMDL05 was generally constant at 57% of the BMD. Benchmark provided a clear advantage in health risk assessment when a LOAEL was the only POD identified, or when dose groups were widely distributed. Although the benchmark method cannot always be applied, in the selected studies with few dose groups it provided a more accurate estimate of the real no-adverse-effect level of a substance.

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