Keeping Pace with Science and Engineering Case Studies in Environmental Regulation (1993) / Chapter Skim
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Formaldehyde Science: From the Laboratory to the Regulatory Arena
Formaldehyde Science: From the Laboratory to the Regulatory Arena
Pages 189-220
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From page 189... ...
While not immediately accepted in all circles, CIIT's initial bioassay data on ECHO ultimately became the foundation of risk assessments used by all of the relevant regulatory agencies. The data left many questions unanswered, however, especially the mechanisms of carcinogenicity and their implications for assessing human risk.
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From page 190... ...
The way in which one interprets the new science can make a big difference in human risk estimates. If the new animal results are incorporated into risk assessments for formaldehyde using one of the most prevalent interpretations of the data, the human risk estimates for the chemical are 10 to 100 times lower than if they are not included.
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From page 191... ...
Two rats developed similar tumors at the next lower exposure level, 5.6 ppm. At the lowest exposure levels, no malignant tumors were apparent.
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From page 192... ...
To complicate matters further, there were no malignant tumors at the lowest exposure levels. What did this imply for the shape of the dose-response curve, particularly at low concentrations?
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From page 193... ...
The first pharmacokinetic studies, performed by Casanova, Heck, and their colleagues at CIIT, explored the relationship between the amount of formaldehyde that the animals were exposed to the administered doseand the dose of the chemical that actually reached the target tissue cells in the rat nose the delivered dose. Using radiolabeled HCHO, the researchers measured the amount of covalent binding of the chemical to rat nasal mucosal DNA and formation of DNA-protein cross-links)
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From page 194... ...
The analysis, summarized in Table 2, showed that cancer risk estimates using the new DPX data were at least an order of magnitude lower than those using the administered doses (Starr and Buck, 1984~. Subsequent studies on glutathione depletion explored the effect of glutathione as a defense mechanism in the formation of DNA-protein crosslinks (Casanova and Heck, 19871.
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From page 195... ...
The monkey DPX data also held significant implications for HCHO cancer risks. The lower rate of cross-link formation and larger target area in the monkey were used to predict a lower cancer risk for primates, and, ultimately, an even lower one for humans than was estimated using the rat data.
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From page 196... ...
Proponents of this view argue that there may be a linear dose-response curve; if so, there would be some potential risk at even the smallest exposure levels. Although there were no tumors seen at the low doses in the animal bioassays, the potential for tumors occurring in a larger sample of rats tested at these concentrations could not be ruled out.
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From page 197... ...
The studies demonstrated that acute and subchronic exposure to formaldehyde induced nasal epithelial lesions and increases in surface cell proliferation rates in rat nasal passages at HCHO concentrations of 6 ppm and higher. As Figure 3 indicates, significant elevations in cell proliferation rates were not detected at concentrations lower than 6 ppm.
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From page 198... ...
Preliminary speculation, however, theorizes that if the cell proliferation data with their potential threshold level were incorporated into the analysis, the risk at low concentrations would be reduced, possibly to zero. The risk estimates for human cancer would be lower.
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From page 199... ...
In an effort to provide more conclusive epidemiologic data on formaldehyde, several large studies were conducted on the chemical in the mid1980s (Blair et al., 1986; Stayner et al., 1988; Vaughan et al., 1986~. These studies were designed specifically to detect moderate elevations in underlying cancer risk among populations with HCHO exposure in the workplace.
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From page 200... ...
The lack of a consistent dose-response relationship was not seen as detracting from the positive findings presented by the study. Critics of Blair's interpretation also argued that the statistically significant excess of lung cancer in workers (who had an exposure latency of at least 20 years)
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From page 201... ...
suggesting that observed human risks were concordant with animal-based risk estimates using administered dose levels. The cancer risk estimates using human data were, however, significantly higher than those obtained using the DPX models (EPA, 1990~.
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From page 202... ...
Consumer Product Safety Commission After the release of the rodent bioassay data, the Consumer Product Safety Commission took the most immediate and ambitious regulatory action. Buoyed by the conclusion that the chemical should be assumed to pose a carcinogenic risk to humans (Federal Panel on Formaldehyde, 1982)
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From page 203... ...
The proposed rulemaking procedure for HCHO that ensued in 1985 was based entirely on the chemical's irritant effects, however, not on its cancer risk (OSHA, 19853. It was not until 1987 that the agency used the CIIT bioassay data in regulatory proceedings, when it lowered its standard for formaldehyde from 3 ppm to 1 ppm as an 8-hour, time-weighted average (OSHA, 1987b)
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From page 204... ...
PUTNAM AND JOHN D GRAHAM While the 1987 rulemaking process for formaldehyde used the bioassay data, it did not incorporate a pharmacokinetic model and the DPX data into OSHA's risk assessments.
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From page 205... ...
In conjunction with the risk management strategy, the agency simultaneously developed a quantitative risk assessment of the health effects of formaldehyde, using both the CIIT bioassay data and the available epidemiologic studies. Written by the Office of Toxic Substances (OTS)
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From page 206... ...
Believing that the recent pharmacokinetic studies were important, the OTS decided that the risk assessment should be updated to include a pharmacokinetic model and the new CIIT data. In the updated risk assessment document released in 1991, the OTS included both the rat and monkey DPX data.
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From page 207... ...
It also pointed out that because of weaknesses in the epidemiologic data, such as possible confounding with simultaneous exposure to particulates, only point estimates with extensive uncertainties were likely to be available. The report recommended that the risk estimates based on the DPX data be compared with those derived from the most appropriate epidemiologic studies, such as the Blair study.
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From page 208... ...
PUTNAM AND JOHN D GRAHAM incorporation of the pharmacokinetic model and DPX data into the risk assessment would lower the estimates of human cancer risk for exposure to formaldehyde.
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From page 209... ...
Opponents2 contend that while the science of pharmacokinetics is a reasonable and promising field in principle, the data on formaldehyde are not yet of sufficient quality to permit the incorporation of a pharmacokinetic model into formal risk analyses. They argue that while the scientific methodologies are improving, the DNA adduct and other measurements are not yet strong enough to be included in human risk estimates.
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From page 210... ...
Sustained cell proliferation, which fixes unstable adducts into mutations, is necessary to get cancerous growths. Just as the DPX data support the view of a nonlinear relationship between administered and delivered dose for formaldehyde, the cell proliferation data posit a nonlinearity in the dose response curve.
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From page 211... ...
A prevalent interpretation and use of the DPX data lowers the risk estimates for human cancer; a prevalent interpretation of the epidemiologic data raises the risk estimates for human cancer. In essence, use of different pieces of the new information results in contrasting risk estimates.
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From page 212... ...
Not only did the data come from a single institute, but the funds to develop them flowed from industries with a distinct interest in lowering the risk estimates for the chemical. On the one hand, one could argue for more studies from diverse institutions to either refute or corroborate the CIIT data for a more balanced generation of the science.
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From page 213... ...
Several additional members were subsequently added to the SAB panel, and, at the new review of the. rick n~.cm~nt the croon was snlit on whether to incorporate the DPX data.
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From page 214... ...
The formaldehyde case demonstrates the power of the courts on several fronts. For example, the federal district court forced future regulatory action by ordering OSHA to consider formally initiating a new rulemaking process for formaldehyde, in response to a suit brought against the agency by several groups seeking an emergency temporary standard for the chemical.
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From page 215... ...
These groups, such as industry associations or public interest advocates, can impact the model at nu Presiclential Philosophy Science T Risk Assessment 1 ' '' Courts l Regulatory Decisions L FIGURE 7 Model of regulatory process: Complication #3.
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From page 216... ...
CIIT, an industry-sponsored research institute, generated both the initial animal bioassay and subsequent DPX data on formaldehyde. Furthermore, CIIT scientists not only adamantly advocated the incorporation of these data into agency risk assessments but also performed and published their own risk assessments using the data.
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From page 217... ...
Sacramento, Calif.:California Air Resources Board.
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From page 218... ...
1988. Expert scientific judgment and cancer risk assessment: A pilot study of pharmacokinetic data.
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From page 219... ...
Comments on the California Air Resources Board proposed identification of formaldehyde as a toxic air contaminant, September 1991, Draft SRP Version. Starr, T
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From page 220... ...
Transcript of the Environmental Health Committee Review of the Draft Risk Assessment Document on Formaldehyde.
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