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. 1991 Feb;91:141–155. doi: 10.1289/ehp.9191141

Comparing alternative approaches to establishing regulatory levels for reproductive toxicants: DBCP as a case study.

W Pease 1, J Vandenberg 1, K Hooper 1
PMCID: PMC1519361  PMID: 2040244

Abstract

This paper compares four alternative approaches for deriving regulatory levels for reproductive toxicants by applying them to the available data on the human spermatotoxicant 1,2-dibromo-3-chloropropane (DBCP). The alternatives examined include the Proposition 65 approach (application of a mandatory 1000-fold uncertainty factor to a no-observed-adverse-effect level [NOAEL]), the Environmental Protection Agency (EPA) approach (application of flexible uncertainty factors to a NOAEL), the Benchmark Dose approach (application of flexible uncertainty factors to a dose associated with a known level of change in a reproductive parameter), and the Quantitative Risk Estimation approach (using low-dose linear extrapolation and a model of the relationship between sperm count and infertility). Applied to DBCP, these approaches do not produce substantially different estimates of allowable exposure levels. However, the approaches do have different data requirements and provide different amounts of information on reproductive hazards to risk managers and the public. Neither the Proposition 65 nor the EPA approach provides information about the extent of health risk remaining at a regulatory level. In contrast, the Benchmark Dose approach can provide estimates of the magnitude of sperm count reduction at a regulatory level, and the Quantitative Risk Estimation approach can provide estimates of exposure-induced infertility.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Amann R. P. Detection of alterations in testicular and epididymal function in laboratory animals. Environ Health Perspect. 1986 Dec;70:149–158. doi: 10.1289/ehp.8670149. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Biava C. G., Smuckler E. A., Whorton D. The testicular morphology of individuals exposed to dibromochloropropane. Exp Mol Pathol. 1978 Dec;29(3):448–458. doi: 10.1016/0014-4800(78)90085-0. [DOI] [PubMed] [Google Scholar]
  3. Bucci L. R., Meistrich M. L. Effects of busulfan on murine spermatogenesis: cytotoxicity, sterility, sperm abnormalities, and dominant lethal mutations. Mutat Res. 1987 Feb;176(2):259–268. doi: 10.1016/0027-5107(87)90057-1. [DOI] [PubMed] [Google Scholar]
  4. Calabrese E. J. Uncertainty factors and interindividual variation. Regul Toxicol Pharmacol. 1985 Jun;5(2):190–196. doi: 10.1016/0273-2300(85)90032-7. [DOI] [PubMed] [Google Scholar]
  5. Cooper R. L., Goldman J. M., Rehnberg G. L. Pituitary function following treatment with reproductive toxins. Environ Health Perspect. 1986 Dec;70:177–184. doi: 10.1289/ehp.8670177. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Crump K. S. A new method for determining allowable daily intakes. Fundam Appl Toxicol. 1984 Oct;4(5):854–871. doi: 10.1016/0272-0590(84)90107-6. [DOI] [PubMed] [Google Scholar]
  7. Dourson M. L., Hertzberg R. C., Hartung R., Blackburn K. Novel methods for the estimation of acceptable daily intake. Toxicol Ind Health. 1985 Dec;1(4):23–33. doi: 10.1177/074823378500100404. [DOI] [PubMed] [Google Scholar]
  8. Dourson M. L., Stara J. F. Regulatory history and experimental support of uncertainty (safety) factors. Regul Toxicol Pharmacol. 1983 Sep;3(3):224–238. doi: 10.1016/0273-2300(83)90030-2. [DOI] [PubMed] [Google Scholar]
  9. Eaton M., Schenker M., Whorton M. D., Samuels S., Perkins C., Overstreet J. Seven-year follow-up of workers exposed to 1,2-dibromo-3-chloropropane. J Occup Med. 1986 Nov;28(11):1145–1150. [PubMed] [Google Scholar]
  10. Egnatz D. G., Ott M. G., Townsend J. C., Olson R. D., Johns D. B. DBCP and testicular effects in chemical workers: an epidemiological survey in Midland, Michigan. J Occup Med. 1980 Nov;22(11):727–732. [PubMed] [Google Scholar]
  11. Fabro S., Shull G., Brown N. A. The relative teratogenic index and teratogenic potency: proposed components of developmental toxicity risk assessment. Teratog Carcinog Mutagen. 1982;2(1):61–76. doi: 10.1002/1520-6866(1990)2:1<61::aid-tcm1770020107>3.0.co;2-o. [DOI] [PubMed] [Google Scholar]
  12. Foote R. H., Berndtson W. E., Rounsaville T. R. Use of quantitative testicular histology to assess the effect of dibromochloropropane (DBCP) on reproduction in rabbits. Fundam Appl Toxicol. 1986 May;6(4):638–647. doi: 10.1016/0272-0590(86)90176-4. [DOI] [PubMed] [Google Scholar]
  13. Foote R. H., Schermerhorn E. C., Simkin M. E. Measurement of semen quality, fertility, and reproductive hormones to assess dibromochloropropane (DBCP) effects in live rabbits. Fundam Appl Toxicol. 1986 May;6(4):628–637. doi: 10.1016/0272-0590(86)90175-2. [DOI] [PubMed] [Google Scholar]
  14. Gaylor D. W. Applicability of cancer risk assessment techniques to other toxic effects. Toxicol Ind Health. 1988 Dec;4(4):453–459. doi: 10.1177/074823378800400404. [DOI] [PubMed] [Google Scholar]
  15. Gaylor D. W. Quantitative risk analysis for quantal reproductive and developmental effects. Environ Health Perspect. 1989 Feb;79:243–246. doi: 10.1289/ehp.8979243. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Gaylor D. W. The use of safety factors for controlling risk. J Toxicol Environ Health. 1983 Mar;11(3):329–336. doi: 10.1080/15287398309530346. [DOI] [PubMed] [Google Scholar]
  17. Glass R. I., Lyness R. N., Mengle D. C., Powell K. E., Kahn E. Sperm count depression in pesticide applicators exposed to dibromochloropropane. Am J Epidemiol. 1979 Mar;109(3):346–351. doi: 10.1093/oxfordjournals.aje.a112687. [DOI] [PubMed] [Google Scholar]
  18. Goldsmith J. R., Potashnik G., Israeli R. Reproductive outcomes in families of DBCP-exposed men. Arch Environ Health. 1984 Mar-Apr;39(2):85–89. doi: 10.1080/00039896.1984.10545840. [DOI] [PubMed] [Google Scholar]
  19. Greenwell A., Tomaszewski K. E., Melnick R. L. A biochemical basis for 1,2-dibromo-3-chloropropane-induced male infertility: inhibition of sperm mitochondrial electron transport activity. Toxicol Appl Pharmacol. 1987 Nov;91(2):274–280. doi: 10.1016/0041-008x(87)90108-6. [DOI] [PubMed] [Google Scholar]
  20. Johnson L., Petty C. S., Neaves W. B. A comparative study of daily sperm production and testicular composition in humans and rats. Biol Reprod. 1980 Jun;22(5):1233–1243. doi: 10.1093/biolreprod/22.5.1233. [DOI] [PubMed] [Google Scholar]
  21. Katz D. F., Diel L., Overstreet J. W. Differences in the movement of morphologically normal and abnormal human seminal spermatozoa. Biol Reprod. 1982 May;26(4):566–570. doi: 10.1095/biolreprod26.4.566. [DOI] [PubMed] [Google Scholar]
  22. Kimmel C. A., Gaylor D. W. Issues in qualitative and quantitative risk analysis for developmental toxicology. Risk Anal. 1988 Mar;8(1):15–20. doi: 10.1111/j.1539-6924.1988.tb01149.x. [DOI] [PubMed] [Google Scholar]
  23. Kimmel C. A., Wellington D. G., Farland W., Ross P., Manson J. M., Chernoff N., Young J. F., Selevan S. G., Kaplan N., Chen C. Overview of a workshop on quantitative models for developmental toxicity risk assessment. Environ Health Perspect. 1989 Feb;79:209–215. doi: 10.1289/ehp.8979209. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Kluwe W. M., Lamb J. C., 4th, Greenwell A. E., Harrington F. W. 1,2-dibromo-3-chloropropane (DBCP)-induced infertility in male rats mediated by a post-testicular effect. Toxicol Appl Pharmacol. 1983 Nov;71(2):294–298. doi: 10.1016/0041-008x(83)90346-0. [DOI] [PubMed] [Google Scholar]
  25. Lantz G. D., Cunningham G. R., Huckins C., Lipshultz L. I. Recovery from severe oligospermia after exposure to dibromochloropropane. Fertil Steril. 1981 Jan;35(1):46–53. doi: 10.1016/s0015-0282(16)45257-x. [DOI] [PubMed] [Google Scholar]
  26. Levine R. J., Symons M. J., Balogh S. A., Arndt D. M., Kaswandik N. T., Gentile J. W. A method for monitoring the fertility of workers. 1. Method and pilot studies. J Occup Med. 1980 Dec;22(12):781–791. doi: 10.1097/00043764-198012000-00011. [DOI] [PubMed] [Google Scholar]
  27. Levine R. J., Symons M. J., Balogh S. A., Milby T. H., Whorton M. D. A method for monitoring the fertility of workers. 2. Validation of the method among workers exposed to dibromochloropropane. J Occup Med. 1981 Mar;23(3):183–188. [PubMed] [Google Scholar]
  28. Lipshultz L. I., Ross C. E., Whorton D., Milby T., Smith R., Joyner R. E. Dibromochloropropane and its effect on testicular function in man. J Urol. 1980 Oct;124(4):464–468. doi: 10.1016/s0022-5347(17)55497-x. [DOI] [PubMed] [Google Scholar]
  29. Låg M., Søderlund E. J., Brunborg G., Dahl J. E., Holme J. A., Omichinski J. G., Nelson S. D., Dybing E. Species differences in testicular necrosis and DNA damage, distribution and metabolism of 1,2-dibromo-3-chloropropane (DBCP). Toxicology. 1989 Oct 2;58(2):133–144. doi: 10.1016/0300-483x(89)90003-6. [DOI] [PubMed] [Google Scholar]
  30. MACLEOD J., GOLD R. Z. The male factor in fertility and infertility. II. Spermatozoon counts in 1000 men of known fertility and in 1000 cases of infertile marriage. J Urol. 1951 Sep;66(3):436–449. doi: 10.1016/S0022-5347(17)74358-3. [DOI] [PubMed] [Google Scholar]
  31. MACLEOD J., GOLD R. Z. The male factor in fertility and infertility. VI. Semen quality and certain other factors in relation to ease of conception. Fertil Steril. 1953 Jan-Feb;4(1):10–33. doi: 10.1016/s0015-0282(16)31142-6. [DOI] [PubMed] [Google Scholar]
  32. MacLeod J., Wang Y. Male fertility potential in terms of semen quality: a review of the past, a study of the present. Fertil Steril. 1979 Feb;31(2):103–116. doi: 10.1016/s0015-0282(16)43808-2. [DOI] [PubMed] [Google Scholar]
  33. Meistrich M. L., Brown C. C. Estimation of the increased risk of human infertility from alterations in semen characteristics. Fertil Steril. 1983 Aug;40(2):220–230. doi: 10.1016/s0015-0282(16)47241-9. [DOI] [PubMed] [Google Scholar]
  34. Meistrich M. L., Samuels R. C. Reduction in sperm levels after testicular irradiation of the mouse: a comparison with man. Radiat Res. 1985 Apr;102(1):138–147. [PubMed] [Google Scholar]
  35. Milby T. H., Whorton D. Epidemiological assessment of occupationally related, chemically induced sperm count suppression. J Occup Med. 1980 Feb;22(2):77–82. doi: 10.1097/00043764-198002000-00003. [DOI] [PubMed] [Google Scholar]
  36. Mortimer D., Templeton A. A., Lenton E. A., Coleman R. A. Semen analysis parameters and their interrelationships in suspected infertile men. Arch Androl. 1982 May;8(3):165–171. doi: 10.3109/01485018208987035. [DOI] [PubMed] [Google Scholar]
  37. Overstreet J. W. Laboratory tests for human male reproductive risk assessment. Teratog Carcinog Mutagen. 1984;4(1):67–82. doi: 10.1002/tcm.1770040108. [DOI] [PubMed] [Google Scholar]
  38. Potashnik G. A four-year reassessment of workers with dibromochloropropane-induced testicular dysfunction. Andrologia. 1983 Mar-Apr;15(2):164–170. doi: 10.1111/j.1439-0272.1983.tb00132.x. [DOI] [PubMed] [Google Scholar]
  39. Potashnik G., Abeliovich D. Chromosomal analysis and health status of children conceived to men during or following dibromochloropropane-induced spermatogenic suppression. Andrologia. 1985 May-Jun;17(3):291–296. doi: 10.1111/j.1439-0272.1985.tb01005.x. [DOI] [PubMed] [Google Scholar]
  40. Potashnik G., Ben-Aderet N., Israeli R., Yanai-Inbar I., Sober I. Suppressive effect of 1,2-dibromo-3-chloropropane on human spermatogenesis. Fertil Steril. 1978 Oct;30(4):444–447. doi: 10.1016/s0015-0282(16)43580-6. [DOI] [PubMed] [Google Scholar]
  41. Potashnik G., Goldsmith J., Insler V. Dibromochloropropane-induced reduction of the sex-ratio in man. Andrologia. 1984 May-Jun;16(3):213–218. doi: 10.1111/j.1439-0272.1984.tb00266.x. [DOI] [PubMed] [Google Scholar]
  42. Potashnik G., Yanai-Inbar I. Dibromochloropropane (DBCP): an 8-year reevaluation of testicular function and reproductive performance. Fertil Steril. 1987 Feb;47(2):317–323. doi: 10.1016/s0015-0282(16)50012-0. [DOI] [PubMed] [Google Scholar]
  43. Potashnik G., Yanai-Inbar I., Sacks M. I., Israeli R. Effect of dibromochloropropane on human testicular function. Isr J Med Sci. 1979 May;15(5):438–442. [PubMed] [Google Scholar]
  44. Rao K. S., Burek J. D., Murray F. J., John J. A., Schwetz B. A., Beyer J. E., Parker C. M. Toxicologic and reproductive effects of inhaled 1,2-dibromo-3-chloropropane in male rabbits. Fundam Appl Toxicol. 1982 Sep-Oct;2(5):241–251. doi: 10.1016/s0272-0590(82)80034-1. [DOI] [PubMed] [Google Scholar]
  45. Sandifer S. H., Wilkins R. T., Loadholt C. B., Lane L. G., Eldridge J. C. Spermatogenesis in agricultural workers exposed to dibromochloropropane (DBCP). Bull Environ Contam Toxicol. 1979 Nov;23(4-5):703–710. doi: 10.1007/BF01770028. [DOI] [PubMed] [Google Scholar]
  46. Søderlund E. J., Brunborg G., Omichinski J. G., Holme J. A., Dahl J. E., Nelson S. D., Dybing E. Testicular necrosis and DNA damage caused by deuterated and methylated analogs of 1,2-dibromo-3-chloropropane in the rat. Toxicol Appl Pharmacol. 1988 Jul;94(3):437–447. doi: 10.1016/0041-008x(88)90284-0. [DOI] [PubMed] [Google Scholar]
  47. Whorton D., Foliart D. DBCP: eleven years later. Reprod Toxicol. 1988;2(3-4):155–161. doi: 10.1016/0890-6238(88)90016-0. [DOI] [PubMed] [Google Scholar]
  48. Whorton D., Milby T. H., Krauss R. M., Stubbs H. A. Testicular function in DBCP exposed pesticide workers. J Occup Med. 1979 Mar;21(3):161–166. [PubMed] [Google Scholar]
  49. Wong O., Whorton M. D., Gordon N., Morgan R. W. An epidemiologic investigation of the relationship between DBCP contamination in drinking water and birth rates in Fresno County, California. Am J Public Health. 1988 Jan;78(1):43–46. doi: 10.2105/ajph.78.1.43. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Wyrobek A. J., Gordon L. A., Burkhart J. G., Francis M. W., Kapp R. W., Jr, Letz G., Malling H. V., Topham J. C., Whorton M. D. An evaluation of human sperm as indicators of chemically induced alterations of spermatogenic function. A report of the U.S. Environmental Protection Agency Gene-Tox Program. Mutat Res. 1983 May;115(1):73–148. doi: 10.1016/0165-1110(83)90015-5. [DOI] [PubMed] [Google Scholar]

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