The mechanistic toxicology of formaldehyde and its implications for quantitative risk estimation.
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Air Pollutants↗
Biomedical subjects
T B Starr
Publications and source records attributed to T B Starr.
Assessing exposure to dinitrotoluene using a biological monitor.
Exposure of workers to dinitrotoluene (DNT) was evaluated at a DNT manufacturing plant. Urine was collected over 72 hours; work diaries were prepared dialy; breathing zone air was sampled; and skin and environmental surfaces were wiped. Chemical analysis was performed using gas chromatography or gas chromatography/mass spectrometry. Proportions of urinary DNT and metabolites deviated substantially from those reported in rats exposed to 2,4-DNT; but as with rats, females appeared to excrete considerably more dinitrobenzyl glucuronide. Between persons on any one day and within persons on different days, considerable variation existed in the proportions of metabolites excreted. The peak rate of excretion was likely to occur toward the end of a work shift or shortly afterward. Most urinary metabolites related to exposure during an eight-hour shift had been excreted by the start of work the following day. Estimates of the maximum one-day exposure incurred by a participant in this study ranged from 0.24 to 1.00 mg of technical-grade DNT per kilogram of body weight. A large proportion of the DNT absorbed by DNT operators and loaders, it is suggested, may have entered through the skin or the gastrointestinal tract.
Animals↗
Differentiation between metabolic incorporation and covalent binding in the labeling of macromolecules in the rat nasal mucosa and bone marrow by inhaled [14C]- and [3H]formaldehyde.
The mechanisms of labeling of macromolecules (DNA, RNA, and protein) in the respiratory and olfactory mucosa, and in the bone marrow (femur) of male Fischer-344 rats exposed to [14C]- and [3H]formaldehyde [( 14C]- and [3H]CH2O) were investigated. Animals were exposed for 6 hr to atmospheres containing [14C]- and [3H]CH2O at concentrations of 0.3, 2, 6, 10, or 15 ppm, 1 day following a single pre-exposure to the same concentration of unlabeled CH2O. The major route of nucleic acid labeling at all concentrations and in all tissues was metabolic incorporation; protein labeling in the respiratory mucosa was mainly due to covalent binding at the higher CH2O concentrations. Incorporation of [14C]CH2O into DNA in the respiratory mucosa was maximal at 6 ppm but decreased at higher concentrations, whereas labeling of DNA in the olfactory mucosa and bone marrow increased monotonically with concentration. Evidence for covalent binding of CH2O to respiratory mucosal DNA was obtained at CH2O concentrations equal to or greater than 2 ppm. The concentration of CH2O covalently bound to DNA at 6 ppm was 10.5-fold higher than at 2 ppm, indicating significant nonlinearity of DNA binding with respect to the inhaled formaldehyde concentration under these conditions. Covalent binding to proteins increased in an essentially linear manner with increases in the airborne concentration. No evidence was obtained for the formation of covalent adducts with macromolecules in the olfactory mucosa or bone marrow. The nonlinear increase in covalent binding to respiratory mucosal DNA with increasing CH2O concentrations may be explained either by a decrease in the efficiency of defense mechanisms or by an increase in the availability of reaction sites on the DNA resulting from increased cell turnover.
Animals↗
The importance of delivered dose in estimating low-dose cancer risk from inhalation exposure to formaldehyde.
Data have recently been obtained on the concentration of formaldehyde covalently bound to the respiratory mucosal DNA of Fischer-344 rats following two 6-hr inhalation exposures to gaseous formaldehyde. These data provide a direct short-term measure of the delivered formaldehyde dose in target tissue as a function of the formaldehyde concentration in ambient air. They also demonstrate that the delivered dose/administered dose relationship is significantly nonlinear. Since chronic inhalation exposure of Fischer-344 rats to high concentrations of gaseous formaldehyde induces squamous cell carcinomas of the nasal cavity, and sine widespread concern exists that formaldehyde exposure may also pose a cancer risk for humans, the implications of this nonlinearity for low-dose risk extrapolation were investigated. The incidence of nasal squamous cell carcinomas in a chronic formaldehyde inhalation bioassay was reanalyzed with several low-dose extrapolation models, using the estimated concentration of formaldehyde covalently bound to respiratory mucosal DNA as the measure of exposure. For this purpose, it was assumed that the short-term observations of covalent binding were representative of steady-state conditions during the course of the chronic study and further, that the covalent binding of formaldehyde to target tissue DNA is an important factor in nasal tumor induction. Resulting maximum likelihood risk estimates and upper 95% confidence bounds were unilaterally lower than the corresponding risk measures based on administered dose, irrespective of the dose-response model employed. Reductions in estimated risk ranged from a factor of 2.5, for the multistage model upper 95% confidence bound, to over 10 orders of magnitude, for the probit model upper 95% confidence bound. These results indicate that the concept of delivered dose can have a significant impact on estimates of low-dose risk and should therefore at least be considered as an alternative dose measure in assessments of human cancer risk from formaldehyde exposure.
Animals↗
Non-linear biological responses to formaldehyde and their implications for carcinogenic risk assessment.
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Animals↗
Assessing effects of occupational exposure on fertility with indirect standardization.
The use of indirect standardization in the assessment of the fertility of occupationally exposed workers is briefly reviewed and critiqued. The calculation of expected births in the method of Levine et al. (J Occup Med 1980;22:781-91) is modified to eliminate negative bias. An example is given using data from a 1977 survey of 60 male workers at a chemical manufacturing plant in Denver, Colorado, who were exposed to dibromochloropropane. The example illustrates how in-plant nonexposed reproductive experience provides a valuable supplement to US fertility tables which are specific only to race, birth cohort, age, and parity. It is also shown, however, that explicit control for potential confounding factors not included in the tables, such as marital status and surgical sterilization, can actually create rather than alleviate confounding error. This occurs when the additional factors co-vary in the reference population with the factors already included in the tables. For martial status, the control-induced error was readily minimized by restricting analysis to married experience at parity one or greater. For surgical sterilization, the corresponding error could not be reduced without severely compromising sample size, and hence control of this potential confounder in similar circumstances is not recommended.
Adolescent↗
Superiority of reproductive histories to sperm counts in detecting infertility at a dibromochloropropane manufacturing plant.
Sperm count distributions among exposed and control groups at a dibromochloropropane (DBCP) manufacturing plant were remarkably similar. Yet reproductive histories from 60 exposed men obtained in conjunction with the semen analyses indicated that fertility had been reduced during exposure. Ratios of observed to expected births or standardized fertility ratios (SFRs) were computed for reproductive experience at parities of 1 or greater. The SFR for the period at risk from DBCP exposure (SFR = 0.63) was significantly lower than those derived from the entire not-at-risk period (SFR = 1.21) or the portion related to nonexposed employment at the plant preceding exposure (SFR = 1.33). Significant reductions would have been evident at least 18 years prior to the year in which the histories were obtained. The effect on fertility seems to have been greatest during the initial period of DBCP production. Most fertility reduction occurred after 3.5 years of exposure. Fertility returned to normal following cessation of exposure (SFR = 1.18), although it appeared to remain subnormal for about two years. Wherever there is concern about the potential for adverse reproductive effects in the workplace, data suitable for fertility analyses should be collected during annual medical examinations.
Adolescent↗