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Styrene Cancer Assessment - Science. George Cruzan, PhD, DABT ToxWorks. Report on Carcinogen Criteria. Reasonably Anticipated to be Human Carcinogen Limited human data, or Sufficient animal data, or Limited animal data, but mechanistic evidence. Human Studies.
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Styrene Cancer Assessment - Science George Cruzan, PhD, DABT ToxWorks
Report on Carcinogen Criteria • Reasonably Anticipated to be Human Carcinogen • Limited human data, or • Sufficient animal data, or • Limited animal data, but mechanistic evidence
Human Studies • Styrene-Butadiene Rubber Workers • Delzell et al., 2006 – No styrene related increases in cancer • Re-interpreted by NTP – Appears to be a Trend for increased non-Hodgkin Lymphoma with styrene exposure • Delzell comment –reason for trend is extremely low NHL rate in unexposed workers in this cohort
Human Studies • Reinforced Plastics and Composite Workers • Ruder et al., 2004 – No styrene-related increase in cancers in 5200 workers • Wong et al., 1994 – No styrene related increase in cancers in 16,000 workers • NTP – studies too small to be meaningful
Human Studies • Reinforced Plastics and Composite Workers • Kogevinas et al. 2004 – Increase in Lymphoma based on average exposure, but not cumulative exposure or duration of exposure • NTP – Average exposure most meaningful; evidence of styrene carcinogenicity
Evaluation of Human Studies • IARC, 2002 – Limited evidence • EU, 2007 – No evidence • ATSDR, 2010 – Inconclusive • NTP – Limited Evidence
Rat Studies • 5 Oral studies negative • 1 Inhalation study increased mammary tumors at exposures of 25-300 ppm • 1 Inhalation study negative at exposures of 600 and 1000 ppm. • 1 Inhalation study – dose-related decrease in mammary tumors – 50 -1000 ppm
Evaluation of Rat Studies • IARC – No evidence of carcinogenicity • EU - No evidence of carcinogenicity • ATSDR - No evidence of carcinogenicity • NTP - Insufficient evidence of carcinogenicity
Oral Mouse Studies • NCI, 1979 – increase trend for lung tumors in males, but within historical control range, “no more than suggestive evidence” • NTP reinterpretation – developed new historical control with lower lung tumors; “clear evidence”
Oral Mouse Studies • NCI, 1979 – mixture of 70%S; 30% b-nitro-S; no increase in lung tumors • Ponomarkov and Tomatis, 1979 – • O20 mice: very toxic: quit dosing after 16 week, 50% mortality; increased lung tumors among survivors • C57 – no increase in lung tumors
Inhalation Mouse Studies • Cruzan et al., 2001 – Increased lung tumors in male and female CD-1 mice. • Mostly benign • Not life-shortening • Not increased at 12 or 18 months
Evaluation of Mouse Studies • IARC – Limited evidence • EU – Limited evidence • ATSDR – Limited evidence • NTP- Sufficient evidence
Are Humans Like Rats or Mice? • Why Lung Tumors in Mice, But Not in Rats?
Metabolism • Most of styrene metabolized by CYP2E1 to styrene oxide (SO) • SO metabolized to mandelic acid or conjugated with glutathione (GSH) • No difference in GSH conjugates between rats and mice • Slightly less mandelic acid in mice
Metabolism • More ring oxidation of styrene in mice • Tumors not directly related to SO • Blood level of SO 100x higher in rats w/o lung tumors than in mice with tumors • In isolated lungs - SO 8x higher in rat lung at n.t. dose than in mouse at t. dose • No lung tumors from SO in mice
Metabolism • Role of CYP2E1 (main metabolism of styrene) • Inhibit CYP2E1 – no reduction in styrene lung toxicity • Genetically remove CYP2E1 (KO) – no reduction in styrene lung toxicity
Metabolism • Role of CYP2F2 (mouse lung metabolism of styrene) • Inhibit CYP2F2 – reduction in styrene lung toxicity • Genetically remove CYP2F2 (KO) – complete elimination of styrene lung toxicity
Styrene Oxide Is Not Toxic Agent From Styrene • SO toxic to lungs in normal (wild-type) mice (have a lot of CYP2F2 in lungs) • SO not toxic in lungs of CYP2F2-KO mice • No CYP2F2, no toxicity from Styrene or SO!
NTP RoC • Limited Evidence in Humans - Reasonably Anticipated • Sufficient Evidence in Animals – Reasonably Anticipated • MOA supports – Reasonably Anticipated
SIRC • Human Data – Inconclusive • Animal Data – Limited to Sufficient • MOA – Mouse Specific • Overall does not support listing