Tuesday, December 30, 2008

Formaldehyde - You Get What You Model For

Sensitivity Analysis of Biologically Motivated Model for Formaldehyde-Induced Respiratory Cancer in Humans

Annals of Occupational Hygiene 2008 52(6):481-495; doi:10.1093/annhyg/men038

Kenny S. Crump1,3,*, Chao Chen2, John F. Fox2, Cynthia Van Landingham1 and Ravi Subramaniam2
1 ENVIRON International Corporation, 1900 North, 18th Street, Suite 804, Monroe, LA 71201, USA2 National Center for Environmental Assessment, Office of Research and Development, US Environmental Protection Agency, Mail Code 8623D, 1200 Pennsylvania Avenue, NW, Washington, DC 20460, USA

"Conolly et al. (2003, 2004) developed biologically motivated models of formaldehyde carcinogenicity in F344 rats and humans based on a two-stage clonal expansion model of cancer. Based on the human model, Conolly et al. (2004) claimed that cancer risks associated with inhaled formaldehyde are deminimis at relevant human exposure levels. However, they did not conduct a sensitivity analysis to evaluate the robustness of this conclusion. Here, we present a limited sensitivity analysis of the formaldehyde human model. We show that when the control animals from the National Toxicology Program (NTP) studies are replaced with control animals only from NTP inhalation studies, estimates of human risk are increased by 50-fold. When only concurrent control rats are used, the model does not provide any upper bound (UB) to human risk. No data went into 20 the model on the effect of formaldehyde on the division rates and death rates of initiated cells. We show that slight numerical perturbations to the Conolly et al. assumptions regarding these rates can be made that are equally consistent with the underlying data used to construct the model, but produce estimates of human risk ranging anywhere from negative up to 10 000 times higher than those deemed by Conolly et al. to be ‘conservative’. Thus, we conclude that estimates of human risk by Conolly et al. (2004) are extremely sensitive to modeling assumptions. This calls into question the basis for the Conolly et al. claim of de minimis human risk and suggests caution in using the model to derive human exposure standards for formaldehyde"

BrooklynDodger(s) comment: There's something up with formaldehyde at EPA. The Dodger(s) believe this activity responds to a TSCA Section 21 Petition by NRDC asking for a rule; EPA denied the petition but announced an assessment. Previously the Dodger(s) have noted the drastic contrasts between inhalation exposure limits by OSHA, NIOSH, ACGIH, and ATSDR, in the context of Katrina trailers and other domicilary exposures. EPA has not set a reference concentration for formaldehyde, having last published an assessment of formaldehyde in IRIS in 1991 which contains a drinking water limit and a cancer unit risk value.

The EPA 1991 (before IARC reclassified formaldehyde as "KNOWN" to be carcinogenic to humans) assessment was:

B1 (Probable human carcinogen - based on limited evidence of carcinogenicity in humans)

Weight-of-Evidence Narrative: Based on limited evidence in humans, and sufficient evidence in animals. Human data include nine studies that show statistically significant associations between site-specific respiratory neoplasms and exposure to formaldehyde or formaldehyde-containing products. An increased incidence of nasal squamous cell carcinomas was observed in long-term inhalation studies in rats and in mice. The classification is supported by in vitro genotoxicity data and formaldehyde's structural relationships to other carcinogenic aldehydes such as acetaldehyde. This may be a synopsis of the full weight-of-evidence narrative. See IRIS Summary.

Quantitative Estimate of Carcinogenic Risk from Oral Exposure Not Assessed under the IRIS Program.

Quantitative Estimate of Carcinogenic Risk from Inhalation Exposure Inhalation Unit Risk(s) Extrapolation Method 1.3 x10-5 per ug/m3 Linearized multistage procedure, additional risk

The Dodger(s) will discuss this at a later time. You haven't heard the last from the Dodger(s) on formaldehyde (or anything else.) Staff from the Chemical Industry Institute of Toxicology (CIIT), now rebranded as the "Hamner Institute for Life Sciences," had published a risk assessment to compete with the EPA quantitative exposure response relationship. The publication above appears to represented an EPA alternative to the CIIT alternative to the EPA calculations. The key finding was that plausible alternative parameters to the CIIT parameters generated unit risks ranging from less than the CIIT estimate to 10,000 higher.

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