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Watson AY, Bates RR, Kennedy D, editors. Air Pollution, the Automobile, and Public Health. Washington (DC): National Academies Press (US); 1988.

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Air Pollution, the Automobile, and Public Health.

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Health Effects of Aldehydes and Alcohols in Mobile Source Emissions


Wayne State University

Aldehydes are oxidation products of alcohols; phenols contain an alcohol functionality attached to an aromatic ring. Although they are structurally related, the chemistry and toxicology of the three classes of compounds are different. From a toxicologic standpoint, aldehydes have been more extensively investigated than alcohols and phenols and constitute the most important health hazard. Thus, most of the emphasis of this chapter is placed on them, but the literature on exposure, health effects, metabolism, and chemistry of aldehydes, alcohols, and phenols are also examined. Recommendations are made for research necessary to fill important gaps in our knowledge of these subjects. The literature review highlights key experiments but is not comprehensive; recent review articles and monographs are cited and can be consulted for more complete information.

Ambient Levels and Production by Mobile Sources

Estimates of the atmospheric levels of some common pollutants present in mobile source emissions and the series of compounds that are discussed in this chapter are presented in table 1. Formaldehyde and acetaldehyde have been monitored more extensively than acrolein, alcohols, and phenols. The data for the latter three compounds represent episodic reports rather than averages of extensive compilations. Nevertheless, they are useful for assigning an order of magnitude to the levels likely to be found in urban air. Formaldehyde is usually the most abundant of the compounds of interest and acetaldehyde is next most abundant. Their concentrations are between 100 and 1,000 times lower than carbon monoxide (CO), the principal pollutant in auto exhaust. Although ambient formaldehyde levels range from 4 to 86 parts per billion (ppb), occasional levels in excess of 1,000 ppb—1 part per million (ppm) —have been reported (Goldsmith and Friberg 1977). Acrolein is usually detected at levels below 10 ppb. Most of the aldehydes in urban air are present as gases. Estimates suggest the percentage of aldehydes bound to particles is approximately 1 percent of the concentration in the gas phase (Grosjean 1982). Acrolein is also produced in fires, but by far the highest concentrations are present in cigarette smoke (12 ppm) (Treitman et al. 1980; Carson et al. 1981). Acetaldehyde is also present in very high concentrations in cigarette smoke (1,650–2,500 ppm) (Elmenhorst and Schultz 1968); the formaldehyde concentration in cigarette smoke is approximately equal to that of acrolein (Newsome et al. 1965).

Table 1.. Atmospheric Levels of Compounds Present in Mobile Source Emissions.

Table 1.

Atmospheric Levels of Compounds Present in Mobile Source Emissions.

Alcohol concentrations in the atmosphere have only been determined in a cursory fashion. In a recent study in urban and rural sampling stations in Arizona, Snider and Dawson (1985) reported values of 7.9 ppb for methanol in Tucson and 2.6 ppb at a location 50 km from Tucson. Atmospheric sampling was by a condensation procedure. The concentrations of ethanol at the two stations were reported to be 3.3 and 0.4 ppb, respectively. The origin of the alcohols was not clear. The authors were unable to detect propanol, butanol, or acrolein. Phenol, as well as o- and m-cresol, have been reported in undiluted auto exhaust at levels of 1.4, 0.2, and 0.3 ppm, respectively (Kuwata et al. 1981).

The ambient levels of aldehydes reported to exist in Los Angeles appear to be higher than levels in other cities in the United States and Japan. Therefore, upper limits can be approximated by studies performed in the Los Angeles metropolitan area. Data gathered at a reporting station in Claremont (~50 km east of Los Angeles) indicate that diurnal patterns exist for formaldehyde and acetaldehyde levels (Grosjean 1982). There is a close correlation between variations in the aldehyde levels and the diurnal fluctuations of ozone (O3) as well as the movement of smog banks. Other reports establish a correlation of fluctuations in aldehyde levels to diurnal variations in CO levels (Cleveland et al. 1977). Diurnal and seasonal fluctuations of formaldehyde and acetaldehyde levels have been observed at a monitoring station on Long Island (Tanner and Meng 1984). These data suggest that mobile sources contribute significantly to ambient concentrations. Estimates of the percentage contribution made by mobile emission sources to the levels of the various compounds are presented in table 1. Such estimates have not been made for alcohols and phenols.

Analysis of the levels of aldehydes in exhaust gases provides evidence for a dependence on the type of engine and fuel (Swarin and Lipari 1983). Table 2 lists the concentrations of formaldehyde and acetaldehyde detected in a 10:1-diluted sample of exhaust gas from an internal combustion engine fueled by gasoline or ethanol. Dramatic increases in acetaldehyde concentrations are detected in ethanol-fueled engine exhaust, as might be expected since acetaldehyde is the two-electron oxidation product of ethanol. Presumably a similar increase in formaldehyde concentrations would be observed in exhaust from engines fueled by methanol.

Table 2.. Concentrations of Formaldehyde and Acetaldehyde in Exhaust Diluted Gases of Internal Combustion Engines Fueled by Gasoline or Ethanol.

Table 2.

Concentrations of Formaldehyde and Acetaldehyde in Exhaust Diluted Gases of Internal Combustion Engines Fueled by Gasoline or Ethanol.

Diesel engines produce significantly higher amounts of aldehydes than do gasoline engines (table 3). Ratios of acetaldehyde to formaldehyde also increase if catalysts are placed in the exhaust stream (Swarin and Lipari 1983). Taken together, these findings suggest that the character of automotive emissions varies dramatically with the type of engine and fuel. This implies that a major shift to, for example, alcohol-containing fuels would have a significant effect on the concentration of certain aldehydes and alcohols in urban air.

Table 3.. Concentrations of Selected Aldehydes in Diluted Diesel Exhaust.

Table 3.

Concentrations of Selected Aldehydes in Diluted Diesel Exhaust.

The levels of alcohols in urban air are rather low, and it is difficult to imagine that they are high enough to exert any health effects. Levels of aldehydes are normally well below levels at which they induce hazardous effects, although they can occasionally reach high ambient concentrations (Grosjean 1982; Beauchamp et al. 1985). Results of test burns indicate that dramatically increased levels of aldehydes are produced from alcohol-containing fuels (Swarin and Lipari 1983). These higher levels could be well within the range that induces adverse health effects. If methanol-and ethanol-based fuels are widely adapted, it will be important to be able to determine the levels of atmospheric aldehydes and to have a baseline value against which to compare them. Thus, routine monitoring should be initiated now.

■ Recommendation 1. Routine monitoring of atmospheric alcohol and aldehyde levels should be performed in regions where alcohol-based fuels are or will be in heavy use.

Reports of the detection of phenols and catechols from mobile source emissions are extremely limited and usually do not provide quantitative information. As a result, knowledge of their levels in urban air and the contribution made by mobile sources is totally inadequate. No realistic risk assessment can be undertaken for this class of compounds without such information.

■ Recommendation 2. Methods should be developed to routinely analyze phenols and catechols in urban air.

Health Effects


The literature on the health effects of aldehydes and alcohols is enormous, but several recent reviews by Consensus Work shop on Formaldehyde (1984), Beauchamp et al. (1985), and Tephly (1985) are particularly appropriate. The present discussion is restricted primarily to inhalation toxicology.

Acute Effects in Humans. Acute irritant effects of aldehydes on human volunteers have been documented. In general, acrolein is the most potent of the series acrolein, formaldehyde, acetaldehyde, crotonaldehyde. For example, acrolein is approximately two to three times more potent than formaldehyde as an irritant (Beauchamp et al. 1985). Table 4 is a compilation of the doses at which various short-term responses to acrolein have occurred in human volunteers (Carson et al. 1981). Ocular and olfactory irritation is the first detectable response and occurs at doses that are 10–20 times higher than the ambient levels in urban air (table 1). Extreme irritation to mucous membranes and alteration in respiration occur at doses approximately 100 times ambient. At such levels, it is likely that irreversible epithelial damage occurs on chronic exposure (see Acute Effects in Rodents, below). A similar profile of effects is observed for formaldehyde in humans at somewhat higher doses. Irritation occurs at 0.1–3.0 ppm, and respiratory difficulties are evident at 10–20 ppm (Fassett 1963). Acetaldehyde and crotonaldehyde are 10–100 times less active than acrolein and formaldehyde.

Table 4.. Acute Effects of Acrolein on Human Volunteers.

Table 4.

Acute Effects of Acrolein on Human Volunteers.

Allergic responses to aldehydes have been reported. Hendrick and Lane (1975) documented a case of asthma induced by exposure of a hospital staff member to formalin vapor. A pronounced decrease in respiratory performance was observed after exposure to a 25 percent solution for 15 min; however, the ambient levels of formaldehyde present were not measured. Symptoms were prevented by pretreatment of the patient with betamethasone. Skin allergies have been induced by topical application of solutions of formaldehyde but the dose responses have not been extensively determined (Maibach 1983). Dermal but not respiratory sensitivity has been observed in guinea pigs exposed to 10 ppm formaldehyde for 6 or 8 hr/day for 5 consecutive days. (Lee et al. 1984).

Chronic Effects in Humans. Numerous groups of individuals are occupationally exposed to formaldehyde, acetaldehyde, acrolein, and crotonaldehyde. Epidemiologic studies of the chronic effects of formaldehyde have been conducted with several of these groups, but the results are inconclusive. Despite the ability to identify exposed individuals, there is little information on their smoking and drinking habits, which confounds the interpretation of any detected alterations in disease incidence. The Consensus Workshop on Formaldehyde (1984) evaluated several epidemiologic studies of professional and industrial workers exposed to formaldehyde and concluded that there are insufficient data to establish whether or not it is a human carcinogen. The level of atmospheric exposure in those workers was approximately 0.1–1.0 ppm. In the same groups, there appeared to be no excess mortality associated with formaldehyde exposure. Chronic exposure of humans to high levels of acrolein is considered unlikely because of its extreme irritation. At levels below those that cause olfactory or respiratory damage (~1 ppm), prolonged exposure to acrolein is intolerable, causing individuals to leave the contaminated environment. Consequently, there is no information on human carcinogenicity or other chronic effects of acrolein, nor are data on potential human carcinogenicity of acetaldehyde or crotonaldehyde available.

Acute and Chronic Effects in Rodents. Pathological changes occur in the upper respiratory, especially nasal, epithelium of rodents exposed to aldehydes. The site and severity are dose dependent (Kutzman et al. 1985). Acute effects have also been noted, and the lesions observed include exfoliation, ciliastasis, cell erosion, ulceration, necrosis, squamous metaplasia, and inflammation (Dalhamn and Rosengren 1971; Buckley et al. 1984). Most of the damage is reversible but some is irreversible. Significantly, these effects are detected when rodents are exposed to the RD50s for formaldehyde and acrolein (Buckley et al. 1984). (The RD50 is defined as the level at which a 50 percent reduction in respiratory rate occurs. This level reflects the stimulation of sensory receptors that attempt to limit exposure to irritants.) The RD50s for formaldehyde and acrolein are 3.1 and 1.7 ppm in mice (Buckley et al. 1984); the RD50 for acrolein is 6.0 ppm in rats (Babiuk et al. 1985). Since pathological changes occur in experimental animals as a result of exposure to the RD50 levels, proposals have been made that the RD50 be used to estimate “safe” exposure levels for humans (possibly 0.01−0.1×RD50) (Kane et al. 1979; Alarie 1981). Whether damage occurs in response to exposure to these much lower levels is unknown.

■ Recommendation 3. Chronic low-dose inhalation toxicology studies should be undertaken to determine if tissue damage occurs in response to exposure to levels of formaldehyde, acetaldehyde, and acrolein that are 10–100 times lower than their RD50s.

Although pure formaldehyde and acrolein do not cause neutrophil recruitment, an inflammatory response has been observed in response to carbon particles coated with either compound (Kilburn and McKenzie 1978). Paradoxically, exposure of suspensions of neutrophils to formaldehyde and acrolein results in lowered responsiveness to soluble stimuli, such as phorbol esters, and decreased generation of superoxide anion (Witz et al. 1985). This may be responsible for the decreased in vivo killing of bacteria by mice treated with either compound (Jakab 1977).

Carcinogenicity. Exposure of 232 Fischer 344 rats to 14.3 ppm formaldehyde (6 hr/day, 5 days/week for 24 months followed by 6 months of nonexposure) induced squamous cell carcinoma in the nasal epithelium of 103 animals (Kerns et al. 1983). Exposure to 5.6 ppm formaldehyde induced squamous cell carcinoma in only 2 of 235 animals, and at 2.0 ppm no response was observed in 236 animals. In mice (B6C3F1), exposure to 14.3 ppm induced nasal tumors in only 2 of 215 animals (Kerns et al. 1983). This figure did not represent a statistically significant increase but is notable because of the rarity of nasal tumors in mice. Exposure of Syrian golden hamsters to 10 ppm formaldehyde (5 hr/ day, 5 days/week for 120 weeks) did not induce any airway tumors (Dalbey 1982). Mixtures of formaldehyde and hydrochloric acid induced nasal cancer in Sprague-Dawley rats that was entirely due to the formaldehyde; no enhancing effect of hydrochloric acid was seen (Albert et al. 1982; Sellakumar et al. 1985). In all of these chronic exposure studies, clearcut evidence was acquired for reversible as well as irreversible damage to respiratory epithelium.

Chronic exposure of groups of Wistar rats (110 animals/group) to acetaldehyde at initial doses of 750, 1,500, or 3,000 ppm (6 hr/day, 5 days/week for 27 months) induced 14, 34, and 38 nasal tumors, respectively, compared to 1 in controls (Woutersen et al. 1984). Severe irreversible degenerative changes of the upper respiratory tract were observed in the high-dose group so the acetaldehyde concentration had to be reduced repeatedly throughout the course of the experiment. The tumors observed at the low and moderate doses of acetaldehyde occurred in the olfactory epithelium (Woutersen et al. 1984), whereas nasal tumors induced by low levels of formaldehyde occur in the respiratory epithelium (Kerns et al. 1983). Nasal tumors induced by high-level exposure to acetaldehyde and formaldehyde occur in the olfactory and respiratory epithelium. The results at low levels suggest that acetaldehyde is better able to penetrate to remote anatomic locations than formaldehyde. Further evidence for differential effects of aldehydes is provided by the observation that acetaldehyde at levels of 1,650–2,500 ppm (7 hr/day, 5 days/week for 52 weeks) induces tracheal, but not nasal, tumors in Syrian golden hamsters (Feron et al. 1982).

Exposure of Syrian golden hamsters to 4 ppm acrolein (7 hr/day, 5 days/week for 52 weeks) induced a number of pathological changes in the upper respiratory tract, particularly the nasal epithelium, but no tumors were observed in any organs (Feron and Kruysse 1977). Acrolein exhibits potent teratogenic and embryolethal effects when it is administered to rats intraamniotically but not by inhalation (Slott and Hales 1985).

Neither acrolein nor formaldehyde was carcinogenic in Syrian golden hamsters (Feron et al. 1982). Acrolein is similar to formaldehyde in chemical reactivity, irritant activity, and retention in the respiratory tract, so it should be tested in the same species in which formaldehyde has been detected as a carcinogen—the rat (Kerns et al. 1983). Attention should be paid to the development of nasal tumors.

■ Recommendation 4. A chronic inhalation toxicology study of acrolein should be undertaken in rats, with emphasis on carcinogenicity.

The species and organ specificities of different aldehydes with respect to their ability to induce respiratory tumors on inhalation exposure is fascinating and has been discussed (Kerns et al. 1983; Swenberg et al. 1983). Stimulation of nasal receptors may play a key role in the difference in the higher sensitivity of rats relative to mice. Rodents attempt to restrict their intake of irritants by reducing their respiratory minute volume (Chang et al. 1981). This response is more pronounced in mice than in rats so, for example, at the same level of exposure to formaldehyde, rats breathe approximately twice as much formaldehyde as mice (Chang et al. 1981). Indeed, the tumorigenic response of mice to the effects of 14.3 ppm formaldehyde is roughly the same as the response of rats to 6 ppm formaldehyde (Kerns et al. 1983). The importance of effective dose on tissue specificity is further emphasized by the observation that no tumors have been detected outside of the respiratory tract with any aldehyde. Studies of the retention (that is, the amount of compound bound to tissue) of various aldehydes in the respiratory tract of dogs indicate that formaldehyde is completely retained and acrolein is nearly completely retained in the upper tract whereas propionaldehyde is much less retained (Egle 1972b). Acetaldehyde is the least retained of all the aldehydes tested in the upper respiratory tract, which is consistent with its ability to induce tumors in hamster trachea (Egle 1972a).

Decreases in minute volume cannot explain the sharpness of the dose response of rats to formaldehyde. However, Swenberg and colleagues (1983) proposed that effects on mucociliary activity may play a role. The nasal respiratory epithelium is normally covered by a dynamic protective layer of mucus. The carbohydrate and protein in this layer may react with molecules such as formaldehyde, preventing their access to epithelial tissue. Interruption of mucous flow might saturate the capacity of these macromolecules to react with formaldehyde over certain anatomic locations, thereby increasing the effective dose. Formaldehyde increases mucous flow at low exposure levels but reduces it at high levels (Swenberg et al. 1983); this may result from the ciliastatic activity exhibited by formaldehyde (Morgan 1983; Morgan et al. 1983). Inhibition of mucociliary clearance introduces an additional step in the carcinogenic process, suggesting that short exposures to high concentrations would be more effective for compound delivery than long exposures to low doses. This is consistent with the nonlinear dose response observed for formaldehyde carcinogenicity in rats. It also suggests that occasional high levels of exposure might exert biological effects not expected from extrapolation of dose responses obtained by chronic low-level exposure (Swenberg et al. 1983). Further support for nonlinearity of formaldehyde action on respiratory epithelium is provided by the dose dependence for induction of squamous metaplasia in the nasal cavity of Fischer 344 rats and B6C3F1 mice (Kerns et al. 1983). Formaldehyde at 2 ppm only induces squamous metaplasia in the anterior-most regions of the nasal cavity in rats. Extensive metaplasia in midlevel and posterior portions of the cavity are observed with 5.6 and 14.3 ppm, respectively. By comparing the extent of squamous metaplasia in mice and rats, it is possible to approximate doses that exert similar pathological effects. Using this criterion, the extent of penetration by formaldehyde appears equivalent in rats and mice at doses of 5.6 and 14.3 ppm, respectively. This result correlates well to the difference in sensitivity of the two species to the carcinogenic action of formaldehyde in the respiratory tract.

Studies indicate that alterations of mucous flow and ciliatoxicity are important components of the nonlinear dose response for the carcinogenic action of formaldehyde (Swenberg et al. 1983). Acrolein exhibits the most potent ciliatoxic activity of any volatile aldehydes (Beauchamp et al. 1985). This may enhance the carcinogenic response to other less ciliatoxic aldehydes such as formaldehyde or acetaldehyde. The most likely combination to test first is acrolein and formaldehyde because they are the most potent ciliatoxins and carcinogens, respectively, in mobile source emissions.

■ Recommendation 5. A chronic inhalation toxicology study of mixtures of formaldehyde and acrolein should be undertaken in rats and hamsters, with emphasis on carcinogenicity.

How one extrapolates the results of carcinogenicity studies in rodents to human exposure is uncertain. Humans are routinely exposed to atmospheric levels of formaldehyde that are 100–1,000 times lower than the doses that induce nasal tumors in rodents. However, individuals in certain cities are intermittently exposed to much higher levels. Whether long-term damage results from these episodic exposures is uncertain, although there is little doubt that acute effects, such as irritation, occur. High intermittent exposure might serve as an initiating event that provides a focus of transformed cells sensitive to promotion by other pollutants or environmental agents. Epidemiologic data do not provide evidence for a significant contribution of air pollution to human cancer but one might suggest that the combination of exposure to aldehydes in automotive emissions with other environmental agents is important in some individuals such as smokers (Doll and Peto 1981). This seems reasonable enough, but the concentrations of aldehydes in cigarette smoke are several orders of magnitude higher than their concentrations in urban air. Therefore, the significance of the contribution of aldehydes in mobile source emissions to health effects in smokers is uncertain. The other complication of extrapolating results from rodent bioassays to humans is the difference in anatomy and physiology of the two species. Rodents are obligate nose breathers whereas humans are not. This has obvious implications for the amounts of toxic agents that reach respiratory tissues by inhalation.

Cultured Cells. Formaldehyde and other aldehydes exert numerous effects on isolated cells in culture. They are toxic to normal as well as tumor cells and, in fact, certain α,β-unsaturated aldehydes were used in human clinical trials as potential chemotherapeutic agents (Schauenstein et al. 1977; Krokan et al. 1985). The genotoxic effects of formaldehyde have long been recognized (Auerbach et al. 1977). It induces single-strand breaks, DNA-protein cross-links, sister chromatid exchanges, and chromosome aberrations (Ross and Shipley 1980; Bedford and Fox 1981; Ross et al. 1981; Fornace 1982; Fornace et al. 1982; Levy et al. 1983). It is mutagenic in a variety of prokaryotic and eukaryotic cells including human fibroblasts (Chanet and von Borstel 1979; Boreiko et al. 1982; Goldmacher and Thilly 1983; Szabad et al. 1983), transforms rodent cells (Ragan and Boreiko 1981), and enhances viral transformation of Syrian hamster embryo cells (Hatch et al. 1983). Formaldehyde-induced DNA lesions appear to be repaired, but formaldehyde itself inhibits the ability of human bronchial epithelial cells and fibroblasts to repair damage by x rays and methylating agents (Grafstrom et al. 1983, 1984). A similar constellation of events occurs in response to treatment of cells with acrolein (Schauenstein et al. 1977; Beauchamp et al. 1985).

Despite the extensive documentation of the cellular effects of formaldehyde and other aldehydes, the understanding of their actions at the molecular level is incomplete. For example, the critical targets that lead to various cellular pathologies are, for the most part, unknown. Evidence exists linking the toxicity of α,β-unsaturated aldehydes to modification of a critical sulfhydryl protein, but its identity is unspecified (Schauenstein et al. 1977). Certain DNA polymerases contain important sulfhydryl groups that are sensitive to modification, so these are likely candidates (Kornberg 1980). Sulfhydryl reactivity may also contribute to the inhibition of DNA repair by methyl transferases caused by formaldehyde (Krokan et al. 1985).

■ Recommendation 6. Experiments should be undertaken in cells cultured from various segments of the upper respiratory tract to determine the mechanisms by which aldehydes exert pathological changes such as toxicity, hyperplasia, ciliatoxicity, and so on.

Such experiments should concentrate on identifying the critical targets for modification by each compound and the extent of modification that triggers the response. For example, despite the extensive literature on killing of prokaryotic and eukaryotic cells by α,β-unsaturated aldehydes, the precise mechanism of killing and the macromolecules involved are uncertain. Does modification of DNA polymerases lead to toxicity or does toxicity result from inhibition of enzymes of ATP generation? At what level of modification does toxicity result? Such knowledge will be important for basic biology as well as for risk assessment based on molecular dosimetry (see below).

A major unresolved question is how one extrapolates the results of experiments demonstrating pathological effects of aldehydes on cultured cells to risk assessment for human exposure. For most of the in vitro experiments, aldehydes are added in solution, whereas in animal exposure experiments they are administered by inhalation. How one relates molar concentrations of liquids to dosages of a gas that may accumulate in a target cell is unknown.


Methanol is rapidly absorbed following oral, cutaneous, or respiratory exposure and undergoes general distribution to body water (Yant and Schrenck 1937; Haggard and Greenberg 1939). Its biological half-life is 1.5–2 hr (Sedivec et al. 1981), which means that many of the toxicologic effects triggered by inhalation exposure may be similar to those observed following oral administration. Methanol's oral toxicity to humans has been known for over 100 years (Tephly 1985). Considerable variability is observed in the dose at which toxicity results but best estimates of a dose required for severe intoxication and death are around 1 g/kg (Roe 1982). A lag phase of 12–24 hr is observed before any symptoms of toxicity are seen, which implies that a metabolite is involved in the toxicity (Tephly 1985). Metabolic acidosis occurs followed by visual effects that can lead to blindness. Ocular toxicity is occasionally followed by coma, other central nervous system effects, and death. Ethanol antagonizes the effects of methanol and it may be that varying amounts of ethanol contamination account for the variability in dose at which methanol is toxic to individuals (Roe 1955). Rodents are not susceptible to the toxic effects of methanol but nonhuman primates are; for example, methanol exhibits ocular toxicity in monkeys (Roe 1982) (see Metabolism, Methanol and Formaldehyde). Exposure of human volunteers to an atmosphere containing 200 ppm methanol results in accumulation of 750 mg of which 50–60 percent is retained in the lung (Sedivec et al. 1981). Considering the dose of methanol estimated to be toxic to humans (1 g/kg), it is unlikely that a normal human being could ever be exposed to enough of it by inhalation to experience acute toxicity.

This author was unable to find carcinogenicity studies of methanol by inhalation exposure. Methanol is metabolized slowly during systemic circulation to formaldehyde, which is quickly metabolized to formic acid (Tephly 1985). A remote possibility is that methanol is oxidized to formaldehyde in the respiratory epithelium which is sensitive to its carcinogenic action. If so, methanol may act as a latent form of formaldehyde leading to accumulation in tissues that formaldehyde is ordinarily inaccessible to. Similar considerations hold for ethanol with respect to acetaldehyde. Taken with the potential importance of methanol and ethanol as alternate fuels, it seems important to test them thoroughly for carcinogenicity via the inhalation route. It is less important to test ethanol in inhalation studies because its oxidation product, acetaldehyde, is 100 times less active as a carcinogen than formaldehyde.

■ Recommendation 7. A chronic inhalation toxicology study of methanol should be undertaken in rats and hamsters, with emphasis on carcinogenicity.

Phenols and Catechols

No information is available on the inhalation toxicology of phenols or catechols. Most toxicologic studies have been performed by oral or intravenous administration, so the concentrations used are difficult to relate to inhalation exposure. Phenols are not strongly toxic, and substituted phenols such as butylated hydroxy toluene and butylated hydroxy anisole are used as preservatives in food. There is some speculation that the presence of phenolic antioxidants in food accounts for the steady decrease in stomach cancer in developed countries since 1945 (Doll and Peto 1981). Indeed, phenolic antioxidants such as butylated hydroxy anisole inhibit chemical carcinogenesis and appear to act at the promotion stage (Slaga et al. 1983). However, high doses of phenolic antioxidants actually appear to be tumor promoters themselves (Ito et al. 1982).

Cocarcinogenic Effects of Aldehydes, Alcohols, and Phenols

Cocarcinogenic effects have been reported for formaldehyde and acetaldehyde (Dalbey 1982; Feron et al. 1982). Lifetime exposure of Syrian golden hamsters to 30 ppm formaldehyde concomitant with subcutaneous administration of 0.5 mg diethylnitrosamine resulted in an enhancement of the number of tracheal tumors over treatment with diethylnitrosamine alone (Dalbey 1982). As mentioned above, formaldehyde does not induce tracheal tumors in hamsters. No enhancement of tumorigenesis was seen in the larynx or lung, and the effect on the trachea was only observed when formaldehyde exposure began before diethylnitrosamine administration. Enhancement did not result when formaldehyde exposure began after diethylnitrosamine injections were completed. A similar experiment was performed in Syrian golden hamsters with acetaldehyde (1,650– 2,500 ppm) and benzo[a]pyrene administered by intratracheal instillation (Feron et al. 1982). At a dose of 36.4 mg but not 18.2 mg benzo[a]pyrene, enhancement of tracheal and bronchial tumorigenesis was observed after 52 weeks. When a similar experiment was performed with injection of diethylnitrosamine no enhancement of tracheal tumorigenesis was observed. In fact, there appeared to be a decrease over controls but this was considered a casual association. Formaldehyde has been reported to exhibit “initiating” and “promoting” activity in the C3H/10T1/2 in vitro transformation system (Ragan and Boreiko 1981; Frazelle et al. 1983).

Methanol has not been tested for cocarcinogenicity by the inhalation route. An epidemiologic association has been established between consumption of alcoholic beverages and esophageal cancer in smokers, but there is no evidence for direct carcinogenicity of ethanol (Doll and Peto 1981). Its role in enhancing the carcinogenicity of cigarette smoke is uncertain. Catechol has been identified as the major cocarcinogenic component of cigarette smoke (Van Duuren and Goldschmidt 1976; Hecht et al. 1981). However, bioassays were performed using the initiation-promotion model on mouse skin so the importance of catechol as an inhalation cocarcinogen is uncertain.

■ Recommendation 8. Attempts should be made to develop an initiation-promotion protocol for carcinogenesis testing of aldehydes and other components of mobile source emissions.

The two-stage mouse skin model has been very useful for detection of potential carcinogens, tumor initiators, and tumor promoters. There is no analogous model that can be used to screen compounds for their effects on respiratory tissues. When aldehydes were administered to rodents simultaneously or after administration of benzo[a]pyrene or diethylnitrosamine (Dalbey 1982; Feron et al. 1982), some stimulatory and inhibitory effects were noted but they were not dramatic, and it was difficult to speculate whether the aldehydes were acting as cocarcinogens or promoters based on the design of the experiments. A reproducible initiation-promotion model would enable rapid testing of mixtures of mobile source emission components by the inhalation route and would provide useful mechanistic information. Considering that formaldehyde and acrolein exert most of their effects on the respiratory epithelium of the nasal tract of rats and that acetaldehyde is a nasal carcinogen in rats and a tracheal carcinogen in hamsters (Feron et al. 1982; Woutersen et al. 1984), efforts should be directed toward developing a model in which the biological effects are monitored in the upper respiratory tract. It appears that most of an inspired dose of these compounds does not reach the bronchi and lungs, so the model should be designed with this in mind. In other words, it would not seem prudent to perform developmental experiments using compounds that exert possible initiating or promoting effects in the lungs.


Although some adverse effects of aldehydes and alcohols have been described in humans, experimental animals, and cell systems, quantification of risk, especially at ambient concentrations, is difficult with the current data base. Additional research is necessary to better estimate the potential toxicity of these compounds. The design and interpretation of experiments will be aided by understanding their metabolism and chemical reactions.

Methanol and Formaldehyde

All of the alcohols and aldehydes considered here are soluble in aqueous and organic solutions, which means they distribute rapidly throughout the body and within cells (Beauchamp et al. 1985). The major pathway of metabolism is oxidative with alcohols oxidized to aldehydes and aldehydes oxidized to acids. For example, methanol is oxidized to formaldehyde, which is oxidized to formic acid:

Image p20003254g589001.jpg


Metabolism of alcohols and aldehydes can result in either detoxification or metabolic activation. The fact that a lag phase is observed before the onset of clinical symptoms of methanol toxicity, coupled with the findings that ethanol and alcohol dehydrogenase inhibitors antagonize methanol toxicity, suggests that a metabolite of methanol is responsible for its observed toxicologic effects. Alcohol dehydrogenase appears to be primarily responsible for the oxidation of methanol (McMartin et al. 1975). Its binding constant for methanol is approximately six times lower than its binding constant for ethanol, which accounts for the ability of ethanol to antagonize methanol's effects (Makar and Tephly 1975). Catalase is important for methanol metabolism in rats but not in monkeys (Mannering and Parks 1957).

The major metabolite of methanol in monkeys is formic acid (eq. 1). Formate also exhibits ocular toxicity in monkeys (Martin-Amat et al. 1978). It accumulates in monkeys following methanol administration, thereby resulting in metabolic acidosis, but does not accumulate in rats. This is consistent with the differential sensitivity of these species to methanol toxicity and implies a role for formate as a toxic metabolite. Methanol oxidation by alcohol dehydrogenase is the rate-limiting step of metabolism and appears to be equally rapid in rats and monkeys (Watkins et al. 1970; Clay et al. 1975). The accumulation of formate in monkeys relative to rats appears to be due to a decreased rate of its oxidation to carbon dioxide (CO2) in monkeys (McMartin et al. 1977). Formate metabolism occurs by a folic acid-dependent pathway, so folate deficiency renders monkeys extremely sensitive to methanol toxicity (McMartin et al. 1977). Conversely, folate supplementation lowers their sensitivity (Noker et al. 1980). It appears that folic acid levels are rate-limiting for formate metabolism to CO2 in monkeys.

The toxic effects of methanol may be enhanced by simultaneous exposure to other compounds. For example, antifolates are used clinically for treatment of psoriasis and cancer, and it is conceivable that individuals undergoing treatment could exhibit enhanced sensitivity to methanol. Acute methotrexate treatment of monkeys does not decrease their rate of formate oxidation, but the effects of chronic treatment are unknown (Noker et al. 1980). Perhaps more important is the observation that nitrous oxide (N2O) is an inhibitor of an enzyme of folic acid metabolism and leads to folate depletion (Eells et al. 1982). Enhanced sensitivity to methanol toxicity is observed following exposure of monkeys to N2O, and metabolic acidosis is induced in rats, a species normally resistant to methanol effects (Eells et al. 1981). This raises the possibility that nitrogen oxides (NO x ) in auto exhaust might enhance any toxic effects of methanol and formaldehyde that are mediated by formic acid.

The oxidation of methanol to formic acid most likely involves formaldehyde as an intermediate (eq. 1). In contrast to the slow rate of its formation from methanol, formaldehyde is oxidized quite rapidly. Its half-life is estimated to be 1 min following intravenous infusion (Reitbrock 1969; McMartin et al. 1979). Formaldehyde does not accumulate following methanol administration but is rapidly metabolized to CO2 (85 percent) and expired (Neely 1964; Mashford and Jones 1982). The initial oxidation of formaldehyde appears to be catalyzed by a formaldehyde dehydrogenase that is glutathione-dependent (Strittmatter and Ball 1955; Goodman and Tephly 1971). The enzyme is quite specific for formaldehyde (Strittmatter and Ball 1955). The remaining 15 percent of formaldehyde that is not oxidized to CO2 may bind to protein or enter pathways of one-carbon metabolism. Formaldehyde does not appear to contribute significantly to methanol toxicity following oral administration.


The major pathway of acrolein metabolism appears to involve conjugation with glutathione followed by conversion to S-carboxyethyl-mercapturic acid (Draminski et al. 1983).

Image p20003254g590001.jpg


Reaction of acrolein with glutathione is a rapid chemical reaction but is also catalyzed by glutathione transferases (Jakoby and Habig 1980). The half-life for conjugation of glutathione with 4-hydroxy-nonenal, a molecule structurally related to acrolein, is approximately 4 sec in perfused rat heart (Ishikawa et al. 1986). Acrolein is also oxidized to acrylic acid in vivo, but this only accounts for approximately 15 percent of the administered dose (Draminski et al. 1983).

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Oxidation of acrolein to acrylic acid by rat liver subcellular fractions is inhibited by diethyldithiocarbamate, an inhibitor of aldehyde dehydrogenase (Patel et al. 1983). Epoxidation of acrolein to glycidaldehyde occurs in rat liver subcellular fractions but it is not known if this transformation takes place in vivo (Patel et al. 1983).

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This is a potentially important metabolite of acrolein because it has been classified as an animal carcinogen (International Agency for Research on Cancer 1976). It induced malignant tumors in rats following subcutaneous injection and papillomas in mice following skin painting (Van Duuren et al. 1965, 1966, 1967). Its role in acrolein metabolism and potential carcinogenicity is uncertain.

Measurement of Inspired Methanol and Formaldehyde

Methanol is produced as a result of normal human metabolism; it is detectable in human breath and urine. The best way to assay for inhaled methanol is to quantitate increases in its urinary levels by gas chromatography. Approximately 1 percent of the inspired dose is excreted in human urine. Because there is a significant background level of methanol in human urine due to metabolism or diet, it has been estimated that the lower limit of exposure to methanol that could be detected by an increase in urinary levels would result from inhalation for 8 hr of air containing 100 ppm methanol (Heinrich and Angerer 1982). On this basis, it is unlikely that one could ever detect increases in methanol inhalation resulting from exposure to mobile source emissions. Considering that formaldehyde is an intermediate in methanol and carbohydrate metabolism, one can extend this analysis to reach the conclusion that it is also impossible to detect inhalation exposure to formaldehyde by monitoring urinary levels of it or its initial metabolite formic acid. This conclusion is strengthened by the realization that formaldehyde does not escape the respiratory tissue to which it is administered and, therefore, never achieves appreciable systemic levels.

Chemical Reactions

Aldehydes. Adduct Formation. Aldehydes are reactive electrophiles that add reversibly to nucleophiles to form covalent hydroxymethyl and imine adducts.

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For simple aliphatic aldehydes such as formaldehyde or acetaldehyde, these adducts are unstable and readily revert to starting materials (Fraenkel-Conrat 1954; Hoard 1960). Thus, despite the fact that formaldehyde is mutagenic, reacts with nucleic acid, and induces major alterations in nucleic acid structure, hydroxymethyl or imine adducts to nucleic acid bases or nucleotides have only recently been isolated and identified (McGhee and von Hippel 1975; Beland et al. 1984). Reaction of hydroxymethyl derivatives with a second nucleotide base produces cross-linked products that are stable to hydrolysis (Feldman 1967).

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Dimeric adducts have been isolated following the reaction of formaldehyde with deoxyguanosine, deoxyadenosine, and deoxycytidine, and mixtures thereof (figure 1) (Feldman 1967; Chaw et al. 1980).

Figure 1.. Adducts formed by reaction of guanosine with formaldehyde, crotonaldehyde, and acrolein.

Figure 1.

Adducts formed by reaction of guanosine with formaldehyde, crotonaldehyde, and acrolein. The formaldehyde adduct is a dimer of two guanosines with a single molecule of formaldehyde. Analogous dimeric adducts are formed by reaction of formaldehyde with (more...)

Chemical reduction of imines generates amines, which are stable.

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Imine reduction probably does not occur in biological systems in vivo but is often used in in vitro experiments to trap unstable aldehyde/nucleophile addition products (Chio and Tappel 1969). It may be useful as a derivatizing reaction for quantitation of aldehyde/protein or aldehyde/nucleic acid adducts that would otherwise decompose during tissue processing and sample preparation.

Addition of nucleophiles to the β-carbon of α,β-unsaturated aldehydes generates products that are considerably stabler than hydroxymethyl compounds or imines.

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The most reactive nucleophile in proteins toward α,β-unsaturated aldehydes is the sulfhydryl group (Schauenstein et al. 1977). Many proteins and enzymes contain sulfhydryl groups, and a detailed study of the toxicity of α,β-unsaturated aldehydes to virus particles, bacteria, and mammalian cells indicates a correlation of their reactivity toward sulfhydryl groups (Schauenstein et al. 1977). The identity of the critical cellular protein inactivated by α,β-unsaturated aldehydes has not been established, but it is noteworthy that two DNA polymerases are reactive toward sulfhydryl reagents (Kornberg 1980). Another candidate is ribonucleotide reductase, which catalyzes the rate-limiting step in cellular DNA synthesis and contains an unusual dithiol group that is sensitive to α,β-unsaturated aldehydes and sulfhydryl reagents (Thelander and Reichard 1979). Finally, it should be mentioned that the tripeptide glutathione contains a sulfhydryl group that reacts readily with α,β-unsaturated aldehydes. In fact, an important physiological role of glutathione is the scavenging of electrophiles such as α,β-unsaturated aldehydes (Jakoby and Habig 1980). Reaction of glutathione with these compounds occurs spontaneously or is enzyme-catalyzed. Although intracellular glutathione concentrations are high (~6 mM), acute exposure to α,β-unsaturated aldehydes can result in significant glutathione depletion, which lowers the cell's defenses toward electrophilic agents (Jakoby and Habig 1980). This is known to potentiate toxicity of xenobiotics in the short term, but the long-term effects of glutathione depletion are unknown.

Adducts between α,β-unsaturated aldehydes and amine groups also form and are biologically very important (eq. 8). Formation of amine-α,β-unsaturated aldehyde adducts is reversible but sufficiently slow that the adducts can be isolated and identified. The structures of several α,β-unsaturated aldehyde/deoxynucleoside adducts have been elucidated and are listed in figure 1. Adducts to deoxyguanosine have been detected following the reaction of acrolein or crotonaldehyde with DNA (Chung and Hecht 1983; Chung et al. 1984). These adducts survive hydrolysis of DNA to deoxynucleosides, which is a key step in the isolation of any DNA adducts. They may represent useful potential indicators of DNA damage in cells exposed to high concentrations of α,β-unsaturated aldehydes. It is interesting that cyclic adducts result from the reaction of α,β-unsaturated aldehydes with DNA bases. Cyclization of the aldehyde group of the initial adduct to a suitably disposed amine group of deoxyguanosine is favored by entropy.

Image p20003254g592002.jpg


A cyclic adduct also forms between deoxyguanosine and glycidaldehyde, an in vitro metabolite of acrolein (Van Duuren and Loewengart 1977).

Reaction of aldehydes with nucleic acids is believed to be responsible for the mutagenic and carcinogenic effects of the compounds. However, saturated and unsaturated aldehydes also inhibit repair of certain adducts formed by methylating agents (Grafstrom et al. 1983, 1984). Inhibition of DNA repair appears to be a result of the covalent reaction of aldehydes with the sulfhydryl group of the methyl acceptor protein that removes the methyl group from O-6-methylguanine residues in DNA exposed to methylating agents. Inactivation of the methyl acceptor protein enhances the mutagenicity of methylating agents. Thus, aldehydes can enhance mutagenesis by a mechanism that does not involve modification of nucleic acid.

Free-Radical Formation. Aldehydes undergo enzyme-catalyzed oxidation and reduction in biological systems. The enzymes involved appear to be dehydrogenases, which implies mechanisms involving hydride transfer—a relatively innocuous transformation. Aldehydes are also prone to autoxidation triggered by one-electron oxidation of the aldehydic carbon-hydrogen bond (Lloyd 1973).

Image p20003254g593001.jpg


The resultant radical couples to O2 under aerobic conditions to form a peroxyl radical.

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The peroxyl radical then carries out one-electron oxidation of another molecule of aldehyde.

Image p20003254g593003.jpg


The latter reactions constitute the propagation steps of a free-radical chain autoxidation. Numerous molecules of aldehyde are oxidized and peroxyl radicals produced as a result of a single initiation event. Peroxyl radicals are relatively stable free radicals that are selective in their reaction with cellular constituents (Willson 1985). They have the ability to diffuse far from the site of their generation to react with specific molecules (Pryor 1984). Acyl peroxyl radicals, the type produced by aldehyde autoxidation, are significantly more reactive than alkyl peroxyl radicals and may not be able to diffuse as far intracellularly. The cellular targets for peroxyl radical reactions are unknown, but they epoxidize isolated double bonds and abstract hydrogen atoms from polyunsaturated fatty acid residues in phospholipids (Willson 1985). The latter reaction results in lipid peroxidation, which can disrupt membrane structure, lead to cell death, and release soluble mediators of toxicity and chemotaxis.

Peroxyl radicals also oxidize sulfides to sulfoxides.

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α-1-Proteinase inhibitor contains a critical methionine residue close to the site that combines with a variety of proteinases to inhibit their action (Travis and Salvesen 1983). Oxidation of the methionine residue abolishes the ability of the protein to inhibit catalysis by proteolytic enzymes. This alters the balance of proteolysis and can have dramatic effects on lung function. The physiological target for α-1-proteinase inhibitor appears to be elastase which degrades pulmonary connective tissue by virtue of its action on elastin. Elastase is secreted by neutrophils in response to their activation during inflammation. The activity of elastase is regulated in part by the amount of α-1-proteinase inhibitor that is available to combine with and inactivate it. Certain genetic diseases that are characterized by pulmonary emphysema are associated with decreased amounts of α-1-proteinase inhibitor (see Wright, this volume). The critical methionine residue of α-1-proteinase inhibitor that controls its activity toward proteinases is oxidized by peroxides and hypochlorous acid, both products of activated neutrophils. It is also oxidized by free radicals such as the one present in cigarette smoke (Pryor 1984). The latter reaction may be especially important in the genesis of diseases associated with chronic cigarette smoking such as emphysema. Although it has not been tested, it seems quite likely that acyl peroxyl radicals formed by autoxidation of aldehydes inactivate α-1-proteinase inhibitor by oxidizing its critical sulfide to a sulfoxide. This provides a mechanism by which one-electron oxidation of aldehydes could lead to pulmonary emphysema.

Alcohols. Alcohols are relatively unreactive chemically with nucleophiles and electrophiles. They can be converted to more reactive derivatives by conjugation with functionalities (for example, glucuronate, sulfate) that render the hydroxyl groups more reactive (Jakoby et al. 1980; Kasper and Henton 1980).

H3C—OH + ·OH → H2Ċ—OH + H2O (14)

These conjugates could conceivably act as electrophiles and alkylate nucleophiles, but there is no evidence that the toxicity exhibited by, for example, methanol is a result of such reactions. Furthermore, short-chain alcohols are highly water-soluble, which removes much of the driving force for their conjugation with polar moieties. Alcohols are oxidized to aldehydes and acids by dehydrogenases, which is a reaction of primary importance in the metabolism of alcohols. Alcohols are not oxidized by one electron to free radicals very readily, although they will react with hydroxyl radical to form hydroxylmethyl radicals.

Phenols and Catechols. Attachment of a hydroxyl group to an aromatic ring greatly enhances the reactivity of the O—H bond. By comparison to aliphatic alcohols, the chemistry of phenols is rich. Phenols are more acidic than alcohols and possess significant nucleophilicity toward reactive electrophiles. For this reason they can serve a protective role as scavengers of metabolically generated electrophiles. They are also conjugated readily, which effects a marked change in their polarity. The most important reaction of phenols is probably with one-electron oxidants (Simic and Hunter 1983). They readily donate electrons of hydrogen atoms, thereby generating phenoxyl radicals.

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Phenoxyl radicals are much more stable than aliphatic alkoxyl radicals because of conjugation with the aromatic ring. Phenols with alkyl substitutents ortho to the hydroxyl group are widely used as chain-breaking antioxidants (Howard 1973). These compounds donate a hydrogen atom to peroxyl radicals that are formed during the propagation step of autoxidation. The stability and steric hindrance of phenoxyl radicals prevent them from abstracting hydrogen atoms from donors that will react with chain-carrying peroxyl radicals. Phenoxyl radicals couple to second molecules of peroxyl radical to form peroxycyclohexadienones.

Image p20003254g594002.jpg


As a result, every phenol molecule removes two peroxyl radicals from autoxidation mixtures, which interrupts the radical chain and inhibits the autoxidation process.

Phenols that lack alkyl groups ortho to the hydroxyl group react with one-electron oxidants to form phenoxyl radicals that are quite reactive. An important reaction of phenoxyl radicals is coupling to O2, which forms peroxyl radicals.

Image p20003254g595001.jpg


As discussed above, peroxyl radicals abstract hydrogen atoms from reactive molecules such as unsaturated fatty acids to initiate and propagate radical-chain oxidations. This leads to the paradox that phenols, which are generally thought to be antioxidants, can actually stimulate free-radical autoxidation. The reactions of phenoxyl radicals are especially important because phenols can be oxidized to phenoxyl radicals by high-valence metals as well as alkoxyl and peroxyl free radicals. This provides a mechanism for metal-catalyzed initiation of free-radical oxidations. Free radicals are believed to enhance carcinogenesis, particularly the promotion phase, and free-radical initiators are promoters in the two-stage assay in mouse skin (Slaga et al. 1981). This may contribute to the reported carcinogenicity of certain phenols in mouse forestomach (Ito et al. 1982) and to the cocarcinogenicity of catechols on mouse skin (Van Duuren and Goldschmidt 1976; Hecht et al. 1981).

Unhindered phenols are oxidized to hydroquinones that are extremely air-sensitive and oxidize to quinones (Irons and Sawahata 1985).

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Quinones are strong electrophiles that undergo addition of nucleophiles to the double bonds of the ring (Irons and Sawahata 1985).

Image p20003254g595003.jpg


This can result in the formation of protein and nucleic acid adducts and to depletion of glutathione. Polycyclic quinones are readily reduced to semiquinones that are either further reduced to hydroquinones or are oxidized by O2 to regenerate the quinone and form O2̅ (Smith et al. 1985). The continuous reduction and oxidation of quinones is called redox cycling and can lead to copious superoxide formation (Smith et al. 1985). This causes DNA strand scission, mutagenicity, and toxicity, all of which probably require metals. Redox cycling may well account for some of the pathophysiological effects of phenols and catechols.

Quantification of Exposure and Estimation of Human Risk

One of the fundamental unsolved problems of toxicology is how to extrapolate dose/ response data obtained in animal testing (usually in rodents) to risk assessment in humans. An approach to crossing this species barrier is to quantitate the dose that reaches the target organ at a series of exposure levels. This is called molecular dosimetry. By knowing the amount of compound that must reach a target cell to exert an effect in, for example, rats, it should be possible to more intelligently estimate the risk of a given amount of the same compound reaching the same cell type in humans. The effective dose that reaches target tissues is more relevant to risk assessment than are the atmospheric levels. For example, at an ambient concentration of 10 ppb, the amount of formaldehyde inspired in 24 hr by an average human is 7 µmole. This does not seem a significant amount until one realizes that it is almost exclusively localized in the mucus and epithelial cells lining the upper respiratory tract.

What is the starting point to be if one is to quantitate binding of aldehydes, alcohols, and phenols to critical intracellular targets for their toxic and carcinogenic effects? Most of the toxicity exhibited by these agents is probably due to covalent binding to protein in which the aldehyde or quinone reacts as an electrophile. There is no doubt that protein binding to these compounds or their metabolites occurs and that it can cause toxicity. Saturated and α,β-unsaturated aldehydes as well as quinones bind rapidly to sulfhydryl proteins and inactivate them. Stable adducts also form to lysine residues. Aldehyde/lysine conjugates have been isolated from rat urine that most likely arise from proteolysis of aldehyde/protein conjugates (McGirr et al. 1985). This provides direct evidence for covalent binding of aldehydes to proteins in vivo. A considerable amount of information suggests that covalent binding to sulfhydryl groups of DNA polymerases is responsible for the toxic effects of α,β-unsaturated aldehydes (Schauenstein et al. 1977). Evidence also suggests that the cytostatic effects of quinones derives from their ability to bind specifically and covalently to tubulin (Irons et al. 1981). A similar reaction of tubulin or another component of the flagellar system may also account for the ciliatoxic activity of aldehydes.

Molecular dosimetry offers an approach to the quantitation of physiologically relevant damage resulting from exposure to aldehydes and quinone metabolites of phenols. Methods could be developed for the analysis of covalent adducts to proteins that are involved in pathological responses in target tissues. Of course, this requires that the key protein targets are known. Understanding the role of individual proteins in toxicologic responses represents a major gap in our knowledge. This is why mechanistic toxicology studies in cell culture are so important. Until an adequate knowledge of key protein targets is available, methods should be designed to quantitate adducts to proteins that are not necessarily important in the observed response but are abundant in the cell or tissue in which the response is observed. This approach is similar to the use of hemoglobin for estimation of exposure to methylating agents and carcinogens. Abundant proteins that contain reactive amine groups would be especially useful because amine/aldehyde conjugates are more stable than thiol/aldehyde conjugates. It is likely that the target cells for the effects of airborne aldehydes are in the epithelial tissue of the nasal and respiratory tracts. This is based on the types of effects observed and the extreme reactivity of the molecules. It is very unlikely that aldehydes or quinones escape pulmonary epithelia to reach peripheral tissues. If most of the covalently bound material is localized in the nasal or respiratory tract, it should be possible to sample these matrices in individual human subjects by lavage techniques.

Molecular dosimetry of nucleic acid adducts in target tissue will be important when attempting to relate inhaled dose to carcinogenic response. Thus, method development is recommended. However, quantitation of nucleic acid adducts in vivo is of less value than quantitation of protein adducts for estimation of inhaled dose. The levels of DNA adducts produced in cells are several orders of magnitude lower than protein adducts and are subject to varying degrees of removal by repair enzymes, which further lowers the steady-state concentration of the nucleic acid adducts.

■ Recommendation 9. Methods should be developed for quantitation of the amounts of aldehydes that reach target organs or potential target organs in humans and rodents.

Despite the long history of investigation of the reaction of formaldehyde with nucleic acids and the knowledge that formaldehyde is a nasal carcinogen, the identity of the adduct(s) that it forms on reaction with DNA in vivo is unknown. This may be due to the hydrolytic instability of imine and hydroxymethyl derivatives of purines and pyrimidines, and it underscores the need for development of novel methods of isolation and analysis. Less is known of the reaction of acetaldehyde and acrolein with DNA although acrolein/deoxyguanosine adducts have been recently identified and detected following the reaction of acrolein with DNA in vitro (Chung et al. 1984). Acrolein is metabolized by microsomal cytochrome P-450 preparations to glycidaldehyde, which binds to DNA and is a carcinogen (International Agency for Research on Cancer 1976; Patel et al. 1983). The adduct that glycidaldehyde forms on reaction with deoxyguanosine is different than the acrolein/deoxyguanosine adducts, so isolation and quantitation of acrolein/DNA adducts following inhalation of acrolein would determine the extent to which metabolism plays a role in acrolein's genotoxic effects in vivo. The availability of methods for detection and quantitation of aldehyde/DNA adducts formed in vivo might be important as part of a molecular dosimetry approach to risk assessment.

■ Recommendation 10. Methods should be developed to detect and quantitate DNA adducts derived from formaldehyde, acetaldehyde, and acrolein. The techniques should then be applied to the detection of DNA adducts formed in target tissues after administration of carcinogenic and subcarcingenic doses of the inhaled compounds. Detection of these adducts in cultured target cells would be a helpful intermediate step in adaption of the analytical methods to detection of in vivo adducts.

There is ample precedent for the importance of electrophilic additions to proteins and nucleic acids in aldehyde and phenol biochemistry and toxicology, but the possibility that free-radical reactions contribute to their health effects has not been rigorously established. Therefore, it would be useful to conduct experiments to probe for the involvement of free radicals as mediators of aldehyde and phenol pathology. This is not a trivial undertaking, because free radicals are species with relatively short half-lives that make them nearly impossible to detect and quantitate directly (usually<1 sec). Nevertheless, it is now possible to trap certain types of free radicals that might be produced from aldehydes and phenols (Packer 1984). In addition, products of in vivo free-radical reactions can be detected and quantitated as indirect evidence for free-radical formation (Packer 1984).

■ Recommendation 11. Experiments should be performed to determine if aldehydes exert toxicologic effects by generation of free radicals.


A review of the literature indicates that aldehydes are the most potent biologically active substances of the compounds under consideration in mobile source emissions. They exert toxicologic effects at concentrations approximately 10–100 times their ambient atmospheric levels. Variations in ambient levels have been reported with occasional toxicologically relevant concentrations reported in heavily polluted metropolitan areas. Inhaled aldehydes exert their toxicologic effects in the upper respiratory tract, and there is no reason to believe that they trigger systemic responses. This may be due to their high reactivity or to the fact that they are rapidly metabolized. Metabolism can result in detoxification or metabolic activation. The formation of substantial amounts of methanol and formaldehyde during normal human metabolism precludes development of analytical methods for their quantitation based on “systemic” approaches, such as plasma or urine analysis. These observations mandate novel approaches to quantitation of exposure and estimation of risk to the human population. Aldehydes and quinones are reactive electrophiles that form adducts with DNA and proteins. The structures of several aldehyde/nucleic acid adducts have been elucidated, but the extent of their formation in vivo is un- vivo. known. Phenols are oxidized to free radicals, which may play a role in tumor promotion. Aldehydes are oxidized to very reactive free radicals in chemical systems but it is uncertain if they form free radicals in biochemical systems in vitro or in

Summary of Research Recommendations


Recommendation 1Routine monitoring of atmospheric alcohol and aldehyde levels should be performed in regions where alcohol-based fuels are or will be in heavy use.
Recommendation 2Methods should be developed to routinely analyze phenols and catechols in urban air.

Health Effects

Recommendation 4A chronic inhalation toxicology study of acrolein should be undertaken in rats, with emphasis on carcinogenicity.
Recommendation 5A chronic inhalation toxicology study of mixtures of formaldehyde and acrolein should be undertaken in rats and hamsters, with emphasis on carcinogenicity.
Recommendation 3Chronic low-dose inhalation toxicology studies should be undertaken to determine if tissue damage occurs in response to exposure to levels of formaldehyde, acetaldehyde, and acrolein that are 10–100 times lower than their RD50s.
Recommendation 8Attempts should be made to develop an initiation-promotion protocol for carcinogenesis testing of aldehydes and other components of mobile source emissions.
Recommendation 7A chronic inhalation toxicology study of methanol should be undertaken in rats and hamsters, with emphasis on carcinogenicity.

Cellular Effects

Recommendation 6Experiments should be undertaken in cells cultured from various segments of the upper respiratory tract to determine the mechanisms by which aldehydes exert pathological changes such as toxicity, hyperplasia, ciliatoxicity, and so on.

Molecular Dosimetry

Recommendation 9Methods should be developed for quantitation of the amounts of aldehydes that reach target organs or potential target organs in humans and rodents.
Recommendation 10Methods should be developed to detect and quantitate DNA adducts derived from formaldehyde, acetaldehyde, and acrolein. The techniques should then be applied to the detection of DNA adducts formed in target tissues after administration of carcinogenic and subcarcingenic doses of the inhaled compounds. Detection of these adducts in cultured target cells would be a helpful intermediate step in adaption of the analytical methods to detection of in vivo adducts.
Recommendation 11Experiments should be performed to determine if aldehydes exert toxicologic effects by generation of free radicals.


  • Alarie, Y. 1981. Bioassay for evaluating the potencyof airborne sensory irritants and predicting acceptable levels of exposure in man, Food Cosmet. Toxi col. 19:623–626. [PubMed: 7308905]
  • Albert, R.E., Sellakumar, A.R., Laskin, S., Kuschner, M., Nelson, N., and Snyder, C.A. 1982. Gaseous formaldehyde and hydrogen chloride induction of nasal cancer in the rat, J. Nat. Cancer Inst. 68:597–603. [PubMed: 6951075]
  • Auerbach, C., Moutschen-Dahman, M., and Moutschen, J. 1977. Genetic and cytogenetical effects of formaldehyde and related compounds, Mutat. Res. 39:317–362. [PubMed: 331091]
  • Babiuk, C., Steinhagen, W.H., and Barrow, C.S. 1985. Sensory irritation response to inhaled aldehydes after formaldehyde pretreatment, Toxicol. Appl. Pharmacol. 79:143–149. [PubMed: 4049401]
  • Beauchamp, R.O., Jr., Andjelkovich, D.A., Kliger man, A.D., Morgan, K.T., and d'A Heck, H. 1985. A critical review of the literature on acrolein toxicity, CRC Crit. Rev. Toxicol 14:309–380. [PubMed: 3902372]
  • Bedford, P., and Fox, B.W. 1981. The role of formaldehyde in methylene dimethylsulphonate-induced DNA cross-links and its relevance to cytotoxicity, Chem.-Biol. Interact. 38:119–126.
  • Beland, F.A., Fullerton, N.F., and Heflich, R.H. 1984. Rapid isolation, hydrolysis, and chromatography of formaldehyde-modified DNA, J. Chroma togr. 308:121–131. [PubMed: 6746809]
  • Boreiko, C.J., Couch, D.B., and Swenberg, J.A. 1982. Mutagenic and carcinogenic effects of formaldehyde, Environ. Sci. Res. 25:353–367.
  • Buckley, L.A., Jiang, X.Z., James R.A., Morgan, K.T., and Barrow, C.S. 1984. Respiratory tract lesions induced by sensory irritants at the RD50 concentration, Toxicol. Appl. Pharmacol. 74:417– 429. [PubMed: 6740688]
  • Carson, B.L., Beall, C.M., Ellis, H.V., Baker, L.H., and Herndon, B.L. 1981. Acrolein Health Effects, NTIS PB82-161282; EPA-68-03-2928; EPA-460/3-81-034, Gov. Rep. Announce. U.S. Index 12.
  • Chanet, R., and von Borstel, R.C. 1979. Genetic effects of formaldehyde in yeast. III. Nuclear and cytoplasmic mutagenic effects, Mutat. Res. 62: 239–253. [PubMed: 388212]
  • Chang, J.C.F., Steinhagen, W.H., and Barrow, C.S. 1981. Effects of single or repeated formaldehyde exposure on minute volume of B6C3F1 mice and F-344 rats, Toxicol. Appl. Pharmacol. 61:451– 459. [PubMed: 7330883]
  • Chaw, Y.F.M., Crane, L.E., Lange, P., and Shapiro, R. 1980. Isolation and identification of cross-links from formaldehyde-treated nucleic acids, Biochemistry 19:5525–5531. [PubMed: 7459328]
  • Chio, K.S., and Tappel, A.L. 1969. Synthesis and characterization of the fluorescent products derived from malonaldehyde and amino acids, Biochemistry 8:2821–2826. [PubMed: 5808334]
  • Chung, F.-L., and Hecht, S.S. 1983. Formation of cyclic 1,N2-adducts by reaction of deoxyguanosine with α-acetoxy-N-nitrosopyrrolidine, 4-(carbethoxynitrosamino) butanal, orcrotonaldehyde, Can cer Res. 43:1230–1235. [PubMed: 6825094]
  • Chung, F.-L., Young, R., and Hecht, S.S. 1984. Formation of cyclic 1,N2-propanodeoxyguanosine adducts in DNA upon reaction with acrolein or crotonaldehyde, Cancer Res. 44:990–995. [PubMed: 6318992]
  • Clay, K.L., Murphy, R.C., and Watkins, W.D. 1975. Experimental methanol toxicity in the primate: analysis of metabolic acidosis in the monkey, Toxicol. Appl. Pharmacol. 34:49–61. [PubMed: 819]
  • Cleveland, W.S., Graedel, T.E., and Kleiner, B. 1977. Urban formaldehyde: observed correlation with source emissions and photochemistry, Atmos. Environ. 11:357–360.
  • Consensus Workshop on Formaldehyde. 1984. Report on the Consensus Workshop on Formaldehyde, Environ. Health Perspect. 58:323–381. [PMC free article: PMC1569424] [PubMed: 6525992]
  • Dalbey, W.E. 1982. Formaldehyde and tumors in hamster respiratory tract, Toxicology 24:9–14. [PubMed: 7135407]
  • Dalhamn, T., and Rosengren, A. 1971. Effect of different aldehydes on tracheal mucosa, Arch. Oto laryngol. 93:496–500. [PubMed: 5554885]
  • Doll, R., and Peto, R. 1981. The Causes of Cancer , pp. 1245–1312, Oxford University Press, Oxford.
  • Draminski, W., Eder, E., and Henschler, D. 1983. A new pathway of acrolein metabolism in rats, Arch. Toxicol. 52:243–247. [PubMed: 6860146]
  • Eells, J.T., Makar, A.B., Noker, P.E., and Tephly, T.R. 1981. Methanol poisoning and formate oxidation in nitrous-oxide treated rats, J. Pharmacol. Exp. Ther. 217:57–61. [PubMed: 7205659]
  • Eells, J.T., Black, K.A., Makar, A.B., Tedford, C.E., and Tephly, T.R. 1982. The regulation of one-carbon oxidation in the rat by nitrous oxide and methionine, Arch. Biochem. Biophys. 219:316–326. [PubMed: 7165305]
  • Egle, J.L., Jr. 1972. a. Retention of inhaled acetaldehyde in the dog, Arch. Environ. Health 24:353– 357. [PubMed: 5021119]
  • Egle, J.L., Jr. 1972. b. Retention of inhaled formaldehyde, propionaldehyde, and acrolein in the dog, Arch. Environ. Health 25:119–124. [PubMed: 5045063]
  • Elmenhorst, H., and Schultz, C.H. 1968. Flüchtige inhaltssotffe des Tabaksrauches. Die chemischen Bestandteile der Gas-Dampf-Phase, Beitr. Tabak forsch. 4:90–123.
  • Fassett, D.W. 1963. Aldehydes and acetals, In: Indus trial Hygiene and Toxicology (F.A.Patty, editor. , ed.), Vol. II , 2nd rev. ed., pp. 1959–1989, Interscience, New York.
  • Feldman, M.Y.A. 1967. Reaction of formaldehyde with nucleotides and ribonucleic acid, Biochim. Biophys. Acta 149:20–34. [PubMed: 5625708]
  • Feron, V.J., and Kruysse, A. 1977. Effects of exposure to acrolein vapor in hamsters simultaneously treated with benzo[a]pyrene or dimethylnitrosamine, J. Toxicol. Environ. Health 3:379–394. [PubMed: 926195]
  • Feron, V.J., Kruysse, A., and Woutersen, R.A. 1982. Respiratory tract tumors in hamsters exposed to acetaldehyde vapour alone or simultaneously to benzo[a]pyrene or dimethylnitrosamine, Eur. J. Cancer Clin. Oncol. 18:13–31. [PubMed: 7200892]
  • Fornace, A.J., Jr. 1982. Detection of DNA single-strand breaks produced during the repair of damage by DNA-protein cross-linking agents, Cancer Res. 42:145–149. [PubMed: 7198506]
  • Fornace, A.J., Jr., Lechner, J.F., Grafstrom, R.C., and Harris, C.C. 1982. DNA repair in humanbronchial epithelial cells, Carcinogenesis 3:1373– 1377. [PubMed: 7151252]
  • Fraenkel-Conrat, H. 1954. Reaction of nucleic acid with formaldehyde, Biochim. Biophys. Acta 15:307– 309. [PubMed: 13208707]
  • Frazelle, J.H., Abernethy, D.J., and Boreiko, C.J. 1983. Weak promotion of C3H10T1/2 cell transformation by repeated treatments with formaldehyde, Cancer Res. 43:3236–3239. [PubMed: 6850633]
  • Goldmacher, V.S., and Thilly, W.G. 1983. Formaldehyde is mutagenic for cultured human cells, Mu tat. Res. 116:417–422. [PubMed: 6835255]
  • Goldsmith, J.R., and Friberg, L.T. 1977. Effects of air pollution on human health. In: Air Pollution , Vol. II (A.C.Stern, editor. , ed.), pp. 457–610, Academic Press, New York.
  • Goodman, J.I., and Tephly, T.R. 1971. A comparison of rat and human liver formaldehyde dehydrogenase, Biochim. Biophys. Acta 252:489–505. [PubMed: 4332837]
  • Grafstrom, R.C., Fornace, A.J., Jr., Autrup, H., Lechner, J.F., and Harris, C.C. 1983. Formaldehyde damage to DNA and inhibition of DNA repair in human cells, Science 220:216–218. [PubMed: 6828890]
  • Grafstrom, R.C., Fornace, A., Jr., and Harris, C.C. 1984. Repair of DNA damage caused by formaldehyde in human cells, Cancer Res. 44:4323–4327. [PubMed: 6467194]
  • Grosjean, D. 1982. Formaldehyde and other carbonyls in Los Angeles ambient air, Environ. Sci. Technol. 16:254–262. [PubMed: 22257249]
  • Haggard, H.W., and Greenberg, L.A. 1939. Studies on the absorption, distribution, and elimination of alcohol. The elimination of methyl alcohol, J. Phar macol. Exp. Ther. 66:479–496.
  • Hatch, G.G., Conklin, P.M., Chrostensen, C.C., Casto, B.C., and Nesnow, S. 1983. Synergism in the transformation of hamster embryo cells treated with formaldehyde and adenovirus, Environ. Muta gen. 5:49–57. [PubMed: 6832085]
  • Hecht, S.S., Carmella, S., Mori, H., and Hoffmann, D.J. 1981. A study of tobacco carcinogenesis. 20. Role of catechol as a major cocarcinogen in the weakly acidic fraction of smoke condensate, J. Nat. Cancer Inst. 66:163–169. [PubMed: 6935456]
  • Heinrich, R., and Angerer, J. 1982. Occupational chronic exposure to organic solvents. X. Biological monitoring parameters for methanol exposure, Int. Arch. Occup. Environ. Health 50:341–349. [PubMed: 7174119]
  • Hendrick, D.J., and Lane, D.J. 1975. Formalin asthma in hospital staff, Br. Med. J. 1:607–608. [PMC free article: PMC1672777] [PubMed: 1125625]
  • Hoard, D.E. 1960. The applicability of formol titration to the problem of end-group determination in polynucleotides. A preliminary investigation, Bio chim. Biophys. Acta 40:62–70. [PubMed: 14402126]
  • Hoshika, Y. 1977. Simple and rapid gas-liquid-solid chromatographic analysis of trace concentrations of acetaldehyde in urban air, J. Chromatogr. 137:455– 460. [PubMed: 881463]
  • Ho ward, J.A. 1973. Homogeneous liquid phase autoxidations, In: Free Radicals (J.K.Kochi, editor. , ed.), Vol. II, pp. 3–62, Wiley-Interscience, New York.
  • International Agency for Research on Cancer. 1976. Glycidaldehyde, In: IARC Monographs on the Eval uation of Carcinogenic Risk of Chemicals to Man , Vol. 11, p. 175 , IARC, Lyon, France.
  • Irons, R.D., and Sawahata, T., 1985. Phenols, catechols, and quinones, In: Bioactivation of Foreign Compounds (M.W.Anders, editor. , ed.), pp. 259–281, Academic Press, New York.
  • Irons, R.D., Neptun, D.A., and Pfeifer, R.W. 1981. Inhibition of lymphocyte transformation and microtubule assembly by quinone metabolites of benzene: evidence for a common mechanism, J. Reticu loendothel. Soc. 30:359–372. [PubMed: 7320996]
  • Ishikawa, T., Esterbauer, H., and Sies, H. 1986. Role of cardiac glutathione transferase and of the glutathione S-conjugate export system in biotransformation of 4-hydroxynonenal in the heart, J. Biol. Chem. 261:1576–1581. [PubMed: 3753704]
  • Ito, N., Hagiwara, A., Shibata, M., Ogiso, T., and Fukushima, S. 1982. Induction of squamous-cell carcinoma in the forestomach of F344 rats treated with butylated hydroxyanisole, Gann 73:332–334. [PubMed: 7117759]
  • Jakab, G.J. 1977. Adverse effect of a cigarette smoke component, acrolein, on pulmonary antibacterial defenses and on viral-bacterial interactions in the lung, Am. Rev. Respir. Dis. 115:33–38. [PubMed: 835891]
  • Jakoby, W.B., and Habig, W.H. 1980. Glutathione transferases, In: Enzymatic Basis of Detoxification (W.B.Jakoby, editor. , ed.), Vol. II, pp. 63–94, Academic Press, New York.
  • Jakoby, W.B., Sekura, R.D., Lyon, E.S., Marcus, C.J., and Wang, J.-L. 1980. Sulfotransferases, In: Enzymatic Basis of Detoxification (W.B.Jakoby, editor. , ed.), Vol. II, pp. 199–228, Academic Press, New York.
  • Kane, L.E., Barrow, C.S., and Alarie, Y. 1979. A short-term test to predict acceptable levels of exposure to airborne sensory irritants, Am. Ind. Hyg. Assoc.J. 40:207–229. [PubMed: 495461]
  • Kasper, C.B., and Henton, D. 1980. Glucuronidation, In: Enzymatic Basis of Detoxification (W.B. Jakoby, editor. , ed.), Vol. II, pp. 3–36, Academic Press, New York.
  • Kerns, W.D., Pavkov, K.L., Donofrio, D.J., Gralla, E.J., and Swedberg, J.A. 1983. Carcinogenicity of formaldehyde in rats and mice after long-term inhalation exposure, Cancer Res. 43:4382–4392. [PubMed: 6871871]
  • Kilburn, K.H., and McKenzie, W.N. 1978. Leukocyte recruitment to airways by aldehyde-carbon combinations that mimic cigarette smoke, Lab. Invest. 38:134–142. [PubMed: 564424]
  • Kornberg, A. 1980. DNA Replication , W.H.Freeman, San Francisco.
  • Krokan, H., Grafstrom, R.C., Sundqvist, K., Esterbauer, H., and Harris, C.C. 1985. Cytotoxicity, thiol depletion, and inhibition of O6-methyl-guanine-DNA methyltransferase by various aldehydes in cultured human bronchial fibroblasts, Carcinogen esis 6:1755–1759. [PubMed: 4064250]
  • Kutzman, R.S., Popenoe, E.A., Schmaeler, M., and Drew, R.T. 1985. Changes in rat lung structure and composition as a result of subchronic exposure to acrolein, Toxicology 34:139–151. [PubMed: 3969686]
  • Kuwata, K., Uebori, M., and Yamazaki, Y. 1981. Reversed-phase liquid chromatographic determination of phenols in auto exhaust and tobacco smoke as p-nitrobenzeneazophenol derivatives, Anal. Chem. 53:1531–1534.
  • Lee, H.K., Alarie, Y., and Karol, M.H. 1984. Induction of formaldehyde sensitivity in guinea pigs, Toxicol. Appl. Pharmacol. 75:147–155. [PubMed: 6464018]
  • Levy, S., Nocentini, S., and Billardon, C. 1983. Induction of cytogenetic effects in human fibroblast cultures after exposure to formaldehyde or X-rays, Mutat. Res. 119:309–317. [PubMed: 6828066]
  • Lloyd, W.G. 1973. Autoxidations, In: Methods in Free Radical Chemistry (E.S.Huyser, editor. , ed.), Vol. 4, pp. 1–131, Marcel Dekker, New York.
  • Maibach, H. 1983. Formaldehyde: effects on animal and human skin, In: Formaldehyde Toxicity (J.E. Gibson, editor. , ed.), pp. 163–174, Hemisphere Publ. Corp., Washington, D.C.
  • Makar, A.B., and Tephly, T.R. 1975. Inhibition of monkey liver alcohol dehydrogenase by 4-methylpyrazole, Biochem. Med. 13:334–342. [PubMed: 813637]
  • Mannering, G.J., and Parks, R.E., Jr. 1957. Inhibition of methanol metabolism with 3-amino-1,2,4-triazole, Science 126:1241–1242. [PubMed: 13495448]
  • Martin-Amat, G., McMartin, K.E., Hayreh, S.S., Hayreh, M.S., and Tephly, T.R. 1978. Methanol poisoning: ocular toxicity produced by formate, Toxicol. Appl. Pharmacol. 45:201–208. [PubMed: 99844]
  • Mashford, P.M., and Jones, A.R. 1982. Formaldehyde metabolism by the rat: a reappraisal, Xenobiot ica 12:119–124. [PubMed: 6806997]
  • McGhee, J.D., and von Hippel, P.H. 1975. Formaldehyde as a probe of DNA structure. I. Reaction with exocyclic amino groups of DNA bases, Bio chemistry 14:1281–1296. [PubMed: 235285]
  • McGirr, L.G., Hadley, M., and Draper, H.H. 1985. Identification of Nα-acetyl-∊-2-propenal lysine as a urinary metabolite of malondialdehyde, J. Biol. Chem. 260:15427–15431. [PubMed: 3934158]
  • McMartin, K.E., Makar, A.B., Martin-Amat, G., Palese, G., and Tephly, T.R. 1975. Methanol poisoning. I. The role of formic acid in the development of metabolic acidosis in the monkey and the reversal by 4-methylpyrazole, Biochem. Med. 13: 319–333. [PubMed: 2163]
  • McMartin, K.E., Martin-Amat, G., Makar, A.B., and Tephly, T.R. 1977. Methanol poisoning. V. Role of formate metabolism in the monkey, J. Pharmacol. Exp. Ther. 201:564–572. [PubMed: 405471]
  • McMartin, K.E., Martin-Amat, G., Noker, P.E., and Tephly, T.R. 1979. Lack of a role for formaldehyde in methanol poisoning in the monkey, Biochem. Pharmacol. 28:645–649. [PubMed: 109089]
  • Morgan, K.T. 1983. Localization of areas of inhibition of nasal mucociliary function in rats following in vivo exposure to formaldehyde, Am. Rev. Respir. Dis. 127:166.
  • Morgan, K.T., Patterson, D.L., and Gross, E.A. 1983. Formaldehyde and the mucociliary apparatus, In: Formaldehyde: Toxicology, Epidemiology and Mech anisms (J.J.Clary, editor; , J.E.Gibson, editor; , and A.S.Waritx, editor. , eds.), Marcel Dekker, New York.
  • Neely, W.B. 1964. The metabolic fate of formaldehyde-14C intraperitoneally administered to the rat, Biochem. Pharmacol. 13:1137–1142. [PubMed: 14222510]
  • Newsome, J.R., Norman, V., and Keith, C.H. 1965. Vapour phase analysis of tobacco smoke, Tob. Sci. 9:102–110.
  • Noker, P.E., Eells, J.T., and Tephly, T.R. 1980. Methanol toxicity: treatment with folic acid and 5-formyltetrahydrofolic acid, Alcohol. Clin. Exp. Res. 4:378–383. [PubMed: 7004236]
  • Packer, L., editor. (ed.) 1984. Methods in Enzymology. Oxygen Radicals in Biological Systems . Academic Press, New York.
  • Patel, J.M., Gordon, W.P., Nelson, S.D., and Leibman, K.C. 1983. Comparison of hepatic biotransformation and toxicity of allyl alcohol and [1,1–2H2]allyl alcohol in rats, Drug Metab. Dispos. 11:164–166. [PubMed: 6133723]
  • Pryor, W.A. 1984. Free radicals in autoxidation and in aging, In: Free Radicals in Molecular Biology, Aging, and Disease (D.Armstrong, editor; , R.S.Sohal, editor; , R.G.Cutler, editor; , and T.F.Slater, editor. , eds.), pp. 13–41, Raven Press, New York.
  • Ragan, D.L., and Boreiko, C.J. 1981. Initiation of C3H/10T1/2 cell transformation by formaldehyde, Cancer Lett. 13:325–331. [PubMed: 7306959]
  • Rietbrock, V. 1969. Kinetik und wege des Methanolumsatzes, Naunyn-Schmiedebergs Arch. Pharmakol. Exp. Pathol. 263:88–105. [PubMed: 4389910]
  • Roe, O. 1955. The metabolism and toxicity of methanol, Pharmacol. Rev. 7:399–412. [PubMed: 13266515]
  • Roe, O. 1982. Species differences in methanol poisoning, CRC Crit. Rev. Toxicol. 10:275–286. [PubMed: 6756793]
  • Ross, W.E., and Shipley, N. 1980. Relationship between DNA damage and survival in formaldehyde-treated mouse cells, Mutat. Res. 79:277–283. [PubMed: 7219432]
  • Ross, W.E., McMillan, D.R., and Ross, C.F. 1981. Comparison of DNA damage by methylmelamines and formaldehyde, J. Nat. Cancer Inst. 67:217–221. [PubMed: 6788992]
  • Schauenstein, E., Esterbauer, H., and Zollner, H. 1977. Aldehydes in Biological Systems , pp. 35–38, Pion Limited, London.
  • Sedivec, V., Mráz, M., and Flek, J. 1981. Biological monitoring of persons exposed to methanol vapours, Int. Arch. Occup. Environ. Health 48:257–271. [PubMed: 7251180]
  • Sellakumar, A.R., Snyder, C.A., Solomon, J.J., and Albert, R.E. 1985. Carcinogenicity of formaldehyde and hydrogen chloride in rats, Toxicol. Appl. Pharmacol. 81:401–406. [PubMed: 4082190]
  • Simic, M.G., and Hunter, E.P.L. 1983. Interactions of free radicals and antioxidants, In: Radioprotectors and Anticarcinogens (O.F.Nygaard, editor; and M.G. Simic, editor. , eds.), pp. 449–460, Academic Press, New York.
  • Slaga, T.J., Klein-Szanto, A.J., Triplett, L.L., Yotti, L.P., and Trosko, J.E. 1981. Skin tumor-promoting activity of benzoyl peroxide, a widely used free radical-generating compound, Science 213: 1023–1025. [PubMed: 6791284]
  • Slaga, T.J., Solanki, V., and Logani, M. 1983. Studies on the mechanism of action of antitumor promoting agents: suggestive evidence for the involvement of free radicals in promotion, In: Radio protectors and Anticarcinogens (O.F.Nygaard, editor; and M.G.Simic, editor. , eds.), pp. 471–485, Academic Press, New York.
  • Slott, V.L., and Hales, B.F. 1985. Teratogenicity and embryolethality of acrolein and structurally related compounds in rats, Teratology 323:65–72. [PubMed: 4035593]
  • Smith, M.T., Evans, C.G., Thor, H., and Orrenius, S. 1985. Quinone-induced oxidative injury to cells and tissues, In: Oxidative Stress (H.Sies, editor. , ed.), pp. 91–114, Academic Press, New York.
  • Snider, J.R., and Dawson, G.A. 1985. Tropospheric light alcohols, carbonyls, and acetonitrile: concentrations in the southwestern United States and Henry's law data, J. Geophys. Res. 90:3797–3805.
  • Strittmatter, P., and Ball, E.G. 1955. Formaldehyde dehydrogenase, a glutathione-dependent enzyme system, J. Biol. Chem. 213:445–461. [PubMed: 14353946]
  • Swarin, S.J., and Lipari, F. 1983. Determination of formaldehyde and other aldehydes by high performance liquid chromatography with fluorescence detection, J. Liq. Chromatogr. 6:425–444.
  • Swenberg, J.A., Barrow, C.S., Boreiko, C.J., d'A Heck, H., Levine, R.J., Morgan, K.T., and Starr, T.B. 1983. Non-linear biological responses to formaldehyde and their implications for carcinogenic risk assessment, Carcinogenesis 4:945–952. [PubMed: 6347426]
  • Szabad, J., Soos, I., Polgar, G., and Hejja, G. 1983. Testing the mutagenicity of malondialdehyde and formaldehyde by the Drosophila mosaic and the sex-linked recessive lethal tests, Mutat. Res. 113: 117–133. [PubMed: 6403850]
  • Tanner, R.L., and Meng, Z. 1984. Seasonal variations in ambient atmospheric levels of formaldehyde and acetaldehyde, Environ. Sci. Technol. 18: 723–726.
  • Tephly, T. 1985. The Toxicity of Methanol and Its Metabolites in Biological Systems, Health Effects Institute Report, Cambridge, Mass.
  • Thelander, L., and Reichard, P. 1979. Reduction of ribonucleotides, Ann. Rev. Biochem. 48:133–158. [PubMed: 382982]
  • Travis, J., and Salvesen, G.S. 1983. Human plasma proteinase inhibitors, Ann. Rev. Biochem. 52:655– 709. [PubMed: 6193754]
  • Treitman, R.D., Burgess, W.A., and Gold, A. 1980. Air contaminants encountered by firefighters, Am. Ind. Hyg. Assoc. J. 41:796–802. [PubMed: 7457369]
  • Van Duuren, B.L., and Goldschmidt, B.M. 1976. Carcinogenic and tumor-promoting agents in tobacco carcinogenesis, J. Nat. Cancer Inst. 56:1237– 1242. [PubMed: 994224]
  • Van Duuren, B.L., and Loewengart, G. 1977. Reaction of DNA with glycidaldehyde. Isolation and identification of a deoxyguanosine reaction product, J. Biol. Chem. 252:5370–5371. [PubMed: 560373]
  • Van Duuren, B.L., Orris, L., and Nelson, N. 1965. Carcinogenicity of epoxides, lactones, and peroxy compounds. II. J. Nat. Cancer Inst. 35:707–717. [PubMed: 5841060]
  • Van Duuren, B.L., Langseth, L., Orris, L., Teebor, G., Nelson, N., and Kuschner, M. 1966. Carcinogenicity of epoxides, lactones, and peroxy compounds. IV. Tumor response in epithelial and connective tissue in mice and rats, J. Nat. Cancer Inst. 37:825–838. [PubMed: 5955045]
  • Van Duuren, B.L., Langseth, L., Goldschmidt, B.M., and Orris, L. 1967. Carcinogenicity of epoxides, lactones, and peroxy compounds. VI. Structure and carcinogenic activity, J. Nat. Cancer Inst. 39:1217–1228. [PubMed: 6079867]
  • Watkins, W.D., Goodman, J.I., and Tephly, T.R. 1970. Inhibition of methanol and ethanol oxidation by pyrazole in the rat and monkey in vivo , Mol. Pharmacol. 6:567–572. [PubMed: 4990046]
  • Willson, R.L. 1985. Organic peroxy free radicals as ultimate agents in oxygen toxicity, In: Oxidative Stress (H.Sies, editor. , ed.), pp. 41–72, Academic Press, New York.
  • Witz, G., Lawrie, N.J., Amoruso, M.A., and Goldstein, B.D. 1985. Inhibition by reactive aldehydes of superoxide anion radical production in stimulated human neutrophils, Chem.-Biol. Interact. 53:13–23. [PubMed: 2986857]
  • Woutersen, R.A., Appleman, L.M., Feron, V.J., and Van Der Heijden, C.A. 1984. Inhalation toxicity of acetaldehyde in rats. II. Carcinogenicity study: interim results after 15 months, Toxicology 31:123–133. [PubMed: 6740689]
  • Yant, W.P., and Schrenck, H.H. 1937. Distribution of methanol in dogs after inhalation of methanol and administration by stomach tube and subcutaneously, J. Ind. Hyg: Toxicol 19:337–345.


Air Pollution, the Automobile, and Public Health. © 1988 by the Health Effects Institute. National Academy Press, Washington, D.C.

Correspondence should be addressed to Lawrence J. Marnett, 435 Chemistry, Wayne State University, Detroit, MI 48202.

Copyright © 1988 by the Health Effects Institute.
Bookshelf ID: NBK218145


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