Module 3 - Strategic case studies in practice

ICH Q3D(R1) Guideline

PDE= 3400 µg/day / 2 = 1700 µg/day

PDE – Inhalation Exposure

Inhaled molybdenum trioxide was carcinogenic in male and female mice (NTP, 1997) and the weight of evidence suggests that calcium and zinc molybdates may be carcinogenic to humans (NAS, 2000). Modeling was conducted using the adenoma/carcinoma incidence data (combined) in female mice (3/50, 6/50, 8/49, and 15/49 for the 0, 10, 30 and 100 mg/m 3 exposure groups, respectively) to determine a linear extrapolation, the unit risk of lung cancer is less than 2.6×10 −5 /μg/m 3 (NAS, 2000). Using a risk level of 1:100000, the inhalation PDE is calculated as follows:

Inhalation PDE

=

1x10 -5

= 0.38 µg/m 3

2.6 x10 -5 /µg/m 3

PDE = 0.38 µg/m 3 / 1000 L/m 3 x 28800 L/d = 10.9 µg/day

No modifying factors are used to adjust a PDE derived by the unit risk approach.

R EFERENCES

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Miller RF, Price NO, Engel RW. Added dietary inorganic sulfate and its effect upon rats fed molybdenum. J Nutr 1956;60(4):539-47.

Murray FJ, Sullivan FM, Tiwary AK, Carey S. 90-Day subchronic toxicity study of sodium molybdate dihydrate in rats. Regul Toxicol Pharmacol 2013: http://dx.doi.org/10.1016/j.yrtph.2013.09.003 (accessed September 29, 2014). NAS. Toxicological risks of selected flame-retardant chemicals: Subcommittee on Flame- Retardant Chemicals, Committee on Toxicology, Board on Environmental Studies and Toxicology, National Academy of Sciences National Research Council. 2000. (available at http://www.nap.edu/catalog/9841.html; accessed March 21, 2014). NTP. Toxicology and carcinogenesis studies of molybdenum trioxide (CAS No. 1313-27-5) in F344 rats and B6C3F1 mice (inhalation studies). National Toxicology Program, Public Health Service, U.S. Department of Health and Human Services. 1997. RIVM. RIVM Report 711701025: Re-evaluation of human-toxicological maximum permissible risk levels. Ruksinstutuut Voor Volksgezondheid En Milieu (National Institute of Public Health and the Environment). 2001. Turnland JR, Keyes WR, Peiffer GL. Molybdenum absorption, excretion, and retention studied with stable isotopes in young men at five intakes of dietary molybdenum. Am J Clin Nutr 1995;62:790-796.

Vyskocil A, Viau C. Assessment of molybdenum toxicity in humans. J Appl Toxicol 1999;19:185-192.

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