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Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals (2001)

Chapter: H Example of a Carcinogenicity Assessment Appendix in a Technical Support Document

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Suggested Citation:"H Example of a Carcinogenicity Assessment Appendix in a Technical Support Document." National Research Council. 2001. Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/10122.
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Appendix H
Example of a Carcinogenicity Assessment Appendix in A Technical Support Document

CARCINOGENICITY ASSESSMENT OF DIMETHYLHYDRAZINE

Slope factors for 1,1-dimethylhydrazine and 1,2-dimethylhydrazine were available but have been withdrawn from the U.S. EPA Integrated Risk Information System (IRIS) (U.S. EPA 1986). For a preliminary carcinogenicity assessment, the withdrawn inhalation slope factor for 1,1-dimethylhydrazine (cited in ATSDR 1994) will be used. The assessment follows previously described methodologies (NRC 1985; Henderson 1992).

The withdrawn slope factor for 1,1-dimethylhydrazine was 3.5 (mg/ kg·d)−1, which, based upon a human inhalation rate of 20 m3/d and a body weight of 70 kg, is equivalent to 1 (mg/m3)−1.

To convert to a level of monomethylhydrazine that would cause a theoretical excess cancer risk of 10−4:

Risk of 1×10−4=(1×10−4/1)×1 mg/m3

=1×10−4 mg/m3 (virtually safe dose)

To convert a 70-y exposure to a 24-h exposure:

Suggested Citation:"H Example of a Carcinogenicity Assessment Appendix in a Technical Support Document." National Research Council. 2001. Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/10122.
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24-h exposure

=d×25,600

=(1×10−4 mg/m3)×25,600 d

=2.56 mg/m3

To account for uncertainty regarding the variability in the stage of the cancer process at which monomethylhydrazine or its metabolites may act, a multistage factor of 6 is applied (Crump and Howe 1984):

(2.56 mg/m3)/6=0.43 mg/m3 (0.18 ppm)

Therefore, based upon the potential carcinogenicity of monomethylhydrazine, an acceptable 24-h exposure would be 0.9 mg/m3 (0.5 ppm).

If the exposure is limited to a fraction (f) of a 24-h period, the fractional exposure becomes 1/f×24 h (NRC 1985).

24-h exposure

=0.43 mg/m3 (0.18 ppm)

8-h

=1.3 mg/m3 (0.5 ppm)

4-h

=2.6 mg/m3 (1.1 ppm)

1-h

=10.3 mg/m3 (4.2 ppm)

0.5 h

=20.6 mg/m3 (8.5 ppm)

Because the AEGL-2 values based upon acute toxicity were equivalent to or lower than the 10−4 risk values derived based on potential carcinogenicity, the acute toxicity data were used for the AEGLs for dimethylhydrazine. For 10−5 and 10−6 risk levels, the 10−4 values are reduced by 10-fold or 100-fold, respectively.

Suggested Citation:"H Example of a Carcinogenicity Assessment Appendix in a Technical Support Document." National Research Council. 2001. Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/10122.
×
Page 194
Suggested Citation:"H Example of a Carcinogenicity Assessment Appendix in a Technical Support Document." National Research Council. 2001. Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/10122.
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Page 195
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Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals contains a detailed and comprehensive methodology for developing acute exposure guideline levels (AEGLs) for toxic substances from inhalation exposures.

The book provides guidance on what documents and databases to use, toxicity endpoints that need to be evaluated, dosimetry corrections from animal to human exposures, selection of appropriate uncertainty factors to address the variability between animals and humans and within the human population, selection of modifying factors to address data deficiencies, time scaling, and quantitative cancer risk assessment.

It also contains an example of a summary of a technical support document and an example of AEGL derivation. This book will be useful to persons in the derivation of levels from other exposure routes—both oral and dermal—as well as risk assessors in the government, academe, and private industry.

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