ACMA/SIRC CA Workshop October 28, 2009

Styrene PEL Issues Cancer – SIRC believes styrene does not cause cancer Reproductive Toxicity – SIRC does not believe styrene is a reproductive toxicant, EU considering OEL based on this. Human Neurotoxicity – These effects occur if exposures are high enough.

Current SIRC Cancer Research Updating Wong (US RPC) cohort study – add at least 15 years of follow-up. Increase “years- at-risk” from ~350,000 to ~500,000. Comparable size (years-at-risk) to Kogevinas Comparable years of follow-up to Ruder (2004) Work to be done by Dow, $182,000, completed by end of 2010.

Current SIRC Cancer Research Mouse Lung Tumors – Manuscript published on mode of action, indicates not relevant for humans – Includes EB, naphthalene, divinylbenzene

Current SIRC Cancer Research Mouse Lung Tumor MOA – MOA proposes styrene metabolized in mouse lung by CYP2F2, leading to different toxic metabolites, and tumors. Much less in rat lung; no effect. Even less in human lung – Developing CYP2F2-KO mice Confirm no toxicity in absence of 2F2 Identify toxic metabolites – they should still be toxic in KO mice

Reproductive Issues SIRC sponsored 2 generation study – reduction in growth at 500 ppm during exposure of F1 offspring; slight reduction in growth of F2 offspring – not directly exposed, very slight (<1 day) retardation in several developmental landmarks. SIRC – effects related to reduced BW in dams. UK proposes OEL of 4 ppm based on effect.

Neurotoxicity Vision Smell Hearing Response

Potential Effects on Vision Color Discrimination – Many studies; some show difference from control population; differences are very small. – Triebig Study – no differences related to styrene exposure – Effects not expected with exposures less than 40 ppm Visual Contrast Sensitivity Triebig Study – no differences related to styrene exposure

Smell Styrene smells Workers exposed to styrene over several years had decreased sensitivity to styrene odor Workers exposed to styrene over several years had NO decreased sensitivity to standard odor (essence of rose) No effect on identification of standard odors

Hearing A few worker studies report deficit in hearing by audiometry – Mostly high frequency – Animal studies also demonstrate (NOAEL = 400 ppm for 4 weeks) A couple of studies report effect exacerbated by noise – Noise in “noise only” and “styrene plus noise” groups were not the same

Hearing Triebig study – Workers exposed for more than 15 years at 30 ppm or greater had reduced hearing at low frequencies by audiometry – Based on Transient Evoked Otoacoutic Emssions (TEOAE) – no styrene effect – NOAEL – 30 ppm?

Neurobehavioral Effect on Symptoms >100 ppm Effect on Mood >100 ppm Effect on Memory and Association >100 ppm

Neurobehavioral Reaction Time – Mutti 1984 – NOAEL 25 ppm (average duration 8 years) – Lindstrom 1992 – No effect at 30 ppm average – Triebig, 1989 –No effect from exposures averaged at 18 ppm (range 3-251) – Cherry, 1980 – NOAEL 92 ppm – Seeber (Triebig), 2009 – No effects up to average of 40 ppm.