Risk assessment for o-toluidine and bladder cancer incidence

Abstract

Background: Elevated bladder cancer incidence has been reported in a cohort of 1875 workers manufacturing chemicals used in the rubber industry and employed any time during 1946-2006. o-Toluidine (OT), an aromatic amine, was the prime suspect agent. Using the available environmental data and process characterization, previous investigators assigned ranks to volatile chemical air concentrations across time in departments and jobs, reflecting probabilities of exposure and use of personal protective equipment for airborne and dermal exposures. Aniline, another aromatic amine, was present at comparable concentrations and is known to be an animal carcinogen but produced lower levels in post-shift urine and of hemoglobin adducts than OT in a group of workers.

Methods: A quantitative risk assessment was performed based on this same population. In this study, cumulative OT exposures were estimated (a) based on previously assigned ranks of exposure intensity and reported actual exposures in jobs with the highest assigned rank, and (b) directly from the historical environmental sampling for OT. Models of bladder cancer incidence were evaluated taking into account possible healthy worker survivor effects.

Results: Under various assumptions regarding workforce turnover, the excess lifetime risk of bladder cancer from OT exposure at 1 ppb was estimated to be in the range 1-7 per thousand.

Conclusions: The current ACGIH TLV and OSHA standards for OT are 2 and 5 ppm, respectively, 1000-fold higher than the exposure estimated here for 1-7 per thousand excess lifetime risk.

Keywords: aromatics amines; bladder cancer; occupational epidemiology; survivor bias.

Figure 1.

Historical association of paired air concentrations of o-toluidine (OTC) with (a) aniline(ANC) and (b) nitrobenzene (NBC) (as natural log in ppm: lnOTC=log[OT], lnANC=log[AN]), and lnNBC=log[NB] reported for workers from a chemical manufacturing plant^,).

Figure 2.

o-Toluidine (OT) air concentrations during 1976–2005 by major departments in a chemical manufacturing plant, as log₁₀(PPM): −1.2 ~ 0.06 ppm OT, −1.1 ~ 0.08 ppm OT, −0.8 ~ 0.16 ppm OT, −0.7 ~ 0.20 ppm OT (source: NIOSH)

Figure 3.

Average o-toluidine and aniline air concentrations by department in a chemical manufacturing plant, March 1990. Source: NIOSH Health Hazard Evaluation (350 μg/m³ ~ 0.08 ppm o-toluidine, 450 μg/m³ ~ 0.10 ppm o-toluidine)

Figure 4.

Association of o-toluidine (OT) urinalysis determinations with OT air concentrations during 1999–2000 in workers from a chemical manufacturing plant. Each plotted point is for means of workers’ paired air/urinalysis samples: arithmetic mean for pre-post change in urine OT (creatinine adjusted, μg/g) and arithmetic mean for air concentration of OT (ppb) compared for same day, department and job, and both plotted on logarithmic scale. Points at −0.1 for urinary OT were (low) samples where post-shift level was lower than per-shift.