ToxicologyLetters, 646.5 (1992) 191-201 0 1992 Elsevier Science Publishers B.V., All rights reserved 03784274/92/$5.00

191

Public health problems of organic solvents M. Ikeda Department

ofPublic

Health, Kyoto University

Faculty ofMedicine,

Kyoto (Japan)

Key words: Organic solvents; Public health

SUMMARY Selected topics of public health importance in toxicology of organic solvents are reviewed. Organic solvents are commonly used as mixtures rather than individual solvents, except for the case of degreasers. Nevertheless, toxicity of mixtures remain mostly to be studied. Among the solvents in general, toluene is apparently the most popular. Narcotic effects are common with all solvents (independent of chemical structure) at high concentrations, and result in an increased incidence of various CNS-related subjective symptoms at concentrations in excess of current occupational exposure limits. Chronic toxicity, teratogenicity and carcinogenicity seems to be related to a given chemical structure. Among the recently reported effects are blindness of “sniffers” by methanol inhalation and teratogenicity of ethylene glycol derivatives in experimental animals. In environmental health, pollution of ground water as well as the general atmosphere by chlorinated hydrocarbons has provoked serious public concern. In addition, emission of certain chemicals including chlorofluorocarbons is recognized to deplete ozone in stratosphere, which may result in human health effects.

INTRODUCTION

Organic solvents are a group of organic compounds of low molecular weight. They have various chemical structures, and include aromatics, aliphatics, chlorinated hydrocarbons, alcohols, ethers, esters, etc. (Table I). Carbon disulfide is also included in some cases because of its similarity in physicochemical properties and, therefore, in use pattern. They share lipophilicity and volatility in common, although some of them are also hydrophilic (e.g. methanol) or less volatile (e.g. cresol). They are used regularly in both developed and developing countries, being used in industries for painting, printing, degreasing etc., and are present in home-use products as, e.g., propellants, coolants, and glue-constituents. Selected topics of public health importance will be reviewed in this presentation. Correspondence to: M. Ikeda, Department of Public Health, Kyoto University Faculty of Medicine, Yoshida-Konoecho, Sakyo-ku, Kyoto 666-01, Japan

192 TABLE

I

CHEMICAL CLASSIFICATION OF ORGANIC SOLVENTS Chemical group

Typical solvents

Aromatics

Benzene*, toluene, xylenes, ethylbenzene, styrene monomer

Chlorinated hydrocarbons

Trichloroethylene, tetrachloroethylene, methylchloroform (or l,l,ltrichloroethane), dichloromethane (methylene chloride)

Alcohols

Methyl alcohol, isopropyl alcohol, butyl alcohol

Ethers

Diethyl ether, 1,Cdioxane

Esters

Methyl acetate, ethyl acetate, butyl acetate

Glycol derivatives

Ethyleneglycol momomethyl ether, ethyleneglycol monoethyl ether, ethyleneglycol monoethyl ether acetate, ethyleneglycol monobutyl ether

Chlorofluorocarbons

Fluorotrichloromethane (CFC-111, 1,1,2~trichloro-1,2,2trifluoroethane (CFC-113)

Miscellaneous

n-Hexane, dimethylformamide, carbon disulfide

Words in parentheses are synonyms. * Use of benzene as a solvent has been limited.

USE PATTERN

Organic solvents are often used as a mixture, and application as a single, unmixed solvent is rather rare. A nation-wide survey was conducted in Japan in order to make this point clear in relation to the use pattern of organic solvents, and to identify popular solvents. In practice, over 1000 solvent products were collected from factories in various industrial regions throughout the country, and they were subjected to analysis by GC [l,Zl. As summarized in Tables II and III, it is evident from the results that most solvent products used in industry such as paints, inks, thinners and adhesives, contain more than one solvent, except for degreasers. In the case of degreasers, they were primarily a single, unmixed preparation; it is known that some chlorinated hydrocarbon degreasers need the addition of stabilizers, up to several percent, for industrial use. The percentage in Table I for mixture type degreasers should be lower when such additives are ignored. Further analysis of the results on the possible use pattern-dependent variation in popularity of solvents (Table III) showed that toluene is the most popular solvent in all the products except for degreasers. The solvent of the 2nd popularity class varied dependent on the product category. Xylenes and ethylbenzene were detected at high percentages, but this high prevalence was due to the their presence as impurities in commercial toluene. Ketones (e.g. methyl ethyl ketone and methyl isobutyl ketone) and ethyl acetate were frequently detected in paints, alcohols in inks and

193 TABLE II COMPLEX COMPOSITION OF SOLVENT-CONTAINING Product

Mixture

No. of samples studied

INDUSTRIAL PRODUCTS Remarks

No.

%

298

205

96%

52

40

77%

Excluding gasoline

Thinner

248

199

86%

Excluding gasoline

Adhesive

120

86

67%

Degreaser

125

70

56%

Paint Ink

Excluding gasoline

Excluding minor stabilizers

Re-tabulated from [1,21. “Mixture” means that the product showed.more than one peak in the gas chromatogram indicating that it consisted of more than one solvent.

TABLE III

POPULAR SOLVENTS IN SOLVENT-CONTAINING Product

PRODUCTS

Popularity 1

2

3

4

5

Paint

To1 (80)

XYl(66)

MEK (26)

MIBK (26)

EA (22)

Ink

To1 (62)

IPA (35)

MeOH (25)

MEK (21)

EA (17)

Thinner

To1 (56)

XYl(33)

EA (38)

EB (32)

MeOH (31)

Adhesive

To1 (51)

n-H (27)

MEK (23)

MeOH (13)

Acet (12)

Degreaser

TRI (14)

MC (14)

MeOH (14)

TET (12)

To1 (8)

Re-tabulated from [1,21. Numbers of samples studied are shown in Table I. Values in the table show prevalence in percent. Abbreviations: Acet, acetone; EA, ethyl acetate; EB, ethylbenzene; IPA, isopropyl alcohol; MC, methylchloroform (l,l,l-trichloroethane); MEK, methyl ethyl ketone; MeOH, methanol; MIBK, methyl isobutyl ketone; n-H, n-hexane; TET, tetrachloroethylene; Tol, toluene; TRI, trichloroethylene; Xyl, xylenes.

n-hexane in adhesives. In contrast, 3 chlorinated hydrocarbons of trichloroethylene (for metal degreasing), tetrachloroethylene (for dry-cleaning and cleaning of plastics) and methylchloroform (a surrogate of the former two solvents) were most popular degreasers and they were used unmixed except for the addition of stabilizing agents. Analyses of glue and other construction materials for hobbies 131disclosed that no toluene, methyl alcohol or ethyl acetate was detected in these products for home-use, as a result of regulation, to prevent sniffing of these 3 solvents in home-use type products.

194 THEORETICAL CONSIDERATION ON TOXICITY

Toxicity of chemicals can be classified into 4 categories, namely: (1) acute toxicity, (2) chronic toxicity, (3) carcinogenicity/mutagenicity/teratogenicity, and (4) eco-toxicity. The fact that organic solvents are applied as a mixture rather than a single component preparation entails the evaluation of toxicity of mixtures, which is however yet to be established. Narcotic effects are the predominant signs of short-term exposure at a high concentration, often leading to death, because the intake of the solvent vapor continues as long as the victim breathes. Accidental acute poisoning or even death of a worker is occasionally reported among those engaged in, e.g., painting in a confined, poorly ventilated space. Narcotic action via inhalation, irritation of the mucous membrane by vapor exposure and defatting effects on the skin by contact with liquid are common to all organic solvents. This is probably related to lipophilicity and not to a specific chemical structure (structure-nonrelated toxicity). In contrast, toxicity as a result of repeated dosing, such as chronic toxicity, teratogenicity and carcinogenicity is apparently related to a given chemical structure (structure-related toxicity). Examples are; (1) hemato-toxicity specific to benzene (absent in alkylated benzene& (2) eye toxicity specific to methanol and methyl acetate (absent in ethanol and other higher alcohols), (3) ployneuropathy associated with the straight six carbon chain structure (e.g., n-hexane and methyl butyl ketone), (4) hepato-toxicity common to some chlorinated hydrocarbons (e.g., carbon tetrachloride and chloroform), (5) testicular toxicity and teratogenicity of some ethylene glycol (EG) derivatives (EC: monomethyl ether, EG monoethyl ether, and their acetate esters), and (6) carcinogenicity (at least in one species of animals) of chlorinated ethylenes (vinyl chloride or monochloroethylene, vinylidene chloride or l,ldichlorocthylene, trichloroethylene and tetrachloroethylene). CNS EFFECTS OF ORGANIC SOLVENTS

It has been well established that organic solvents when inhaled, especially at high concentrations, show suppressive effects on the central nervous system (CNS). At lower concentrations, as encountered in occupational settings, the effects are manifested as increased seemingly CNS-related subjective symptoms. For example, in an epidemiological study on 452 workers exposed predominantly (i.e. (90% on a ppm basis) to toluene and 517 nonexposed controls, subjective symptoms during work (e.g. dizziness

195

and floating sensation) and when not at work (nausea, inability to concentrate, etc.) increased in close association with exposure intensity, with a possible threshold at 100 ppm for the former and 50-100 ppm for the latter

[41. Itis also known that repeated and prolonged exposuro to solvent vapor e.g. by inhalation to enjoy a brief ‘high’ &o-called glue- or thi~er-anise) will result in toxic e~~eph~opathy. Knox and Nelson E51reported the first such case. The neurological signs included ataxia, emotional lability and positive Babinski reflex, and the brain damage was confirmed by electroencephalography and pneumoencephalography. A number of cases have been reported since then (e.g. [61), producing serious social problems in many countries. Whereas there is less argument on the observation that organic solvents at very high doses cause en~e~h~opathy, the question was raised of the possible induction of brain damage (chronic toxic en~ep~lopathy~ following occupational exposure, i.e., lower levels of exposure for longer periods. This issue was debated in 1970s and 1980s 17-101. Of the two latest reports, one is on the comparison of 557 cases (all men) with death certificates bearing presenile dementia as cause of death and sex- and agematched control cases. The study showed no significant difference between the two groups as regards estimated occupational exposure to organic solvents fl II I The other is on neu~beba~or~ effects of organic solvents at low level after long-term occupational exposure at up to 27 ppm (a group mean of total hydrocarbons, i.e., toluone, methyl ethyl ketone, etc.). Only subclinical neurobehavioral effects were detected in a dose-related manner 1121.Thus, it appears likely that the possibility is remote for chronic toxic encephalopathy to be induced under normal modern occupational conditions.

Since early reports in the 1910s (e.g. Cl31) on blindness among methanolexposed workers engaged in shellacking the interior of beer vats, there have been no further reports in recent years, until amblyopia cases were discovered among sniffers who abused thinner preparations which contained methanol and methyl acetate 113,141, or methanol 1151 @able fVj. Experiments to reproduce sniffing conditions have been reported with methanol vapor concentrations ranging from 12 000 to 13 000 ppm. These concentrations were much higher than the thinner composition would suggest [15,161. The importance of co-existing methyl acetate was also stressed 114,151 as this solvent is readily hydrolyzed in the body to methanol. It is true that the concentrations detected by the simulation were much higher than the levels in factories, Nevertheless, these cases are worthy of

196 TABLE IV CASES OF AMBLYOPIA INDUCED BY METHANOL INHALATION Case

Sex

Age @ears)

Sniffing historya Visual disturbance

Ref.

1

Man

21

3 days

Complete blindness

14

2

Woman

17

3 months

Complete blindness

15

3

Man

32

2 years?

Blurred vision

16

‘Sniffing of the suspected solvent preparation.

attention in the sense that they clearly demonstrate that methanol (and possibly also methyl acetate) is toxic to the eye not only when ingested but when inhaled at least at high concentrations. REPRODUCTIVE TOXICITY OF ETHYLENE GLYCOL DERIVATIVES

A group of ethyleneglycol (EG) ethers and their acetate esters, i.e., EG monomethyl ether (EGME), EGME acetate (EGMA), EG monoethyl ether (EGEE) and EGEE acetate (EGEA) are unique in the sense that they are toxic to the testis when given to males and teratogenic when given to females. As early as 1979, Nagano et al. [171 observed a significant testicular atrophy in mice given EGEE orally. Later studies confirmed that testicular toxicity is common with its homologue EGME and acetate esters (EGMA and EGEA). They all exhibit teratogenicity (e.g. [18,191). An example is summarized in Table V. It appears that fetotoxicity (including teratology and testicular hypoplasia) is detectable in rats and mice even in the absence of apparent maternal toxicity [Ml. When male animals were exposed to EGME vapor for 6 h/day, 5 days/week for 13 weeks, a virtual no-adverse-effect level for testicular effect was 30 ppm for rabbits, whereas no effect was detectable at this concentration in rats D91. While these solvents are poorly volatile, they can be absorbed through healthy human skin 1201. In an epidemiology study on male workers potentially exposed to EGME, however, no significant changes in fertility indices were detected except for possible (statistically insignificant) smaller testicular size. EGME concentrations, by personal and stationary sampling in a packaging and distribution building, studied were 5-9 ppm and 4-20 ppm, respectively 1211.In a separate study on semen quality of 37 male workers exposed to EGEE at 6.6 ppm (geometric mean) and 39 nonexposed controls, it was found that there was no significant difference in semen volume, sperm viability, motility and velocity, or testicular volume, although the mean sperm count per ejaculate was lower in the exposed than in the controls and some ‘differences in the proportion of abnormal sperm shapes were observed [221.

197

TABLEV TERATOGENICITY OFETHYLENEGLYCOL MONOMETHYL ETHER Parameter

Maternal Bodyweightgain Reproductive Resorptionrate Fetal Bodyweight Morphology

Animalspecies Rat

Mouse

Rabbit

Decrease(transient)

Decrease(transient)

Decrease

-

-

Increase

-

-

Decrease

Fetotoxic

Fetotoxic

Pregnantanimalswereexposedto the vaporat 50 ppmfor 6 b/day on days 6-15 (rats and mice)or 6-18 (rabbits).Rearrangedfrom 1181. ENVIRONMENTAL POLLUTION BY CHLORINATED HYDROCARBONS Trichloroethylene and tetrachloroethylene have been widely used in many countries for years, predominantly for metal degreasing, and drycleaning, respectively. Both solvents are carcinogenic at least in mice and produce hepatocellular carcinoma after repeated large dose administration by gavage (e.g. [231). In addition, the potency to induce malignant tumors by inhalation has also been proved 124,251. Occupational epidemiology suggests no definite evidence of any cancer incidence among tri- or tetra-chloroethylene-exposed workers 1261. Two recent studies, however, report an elevated risk of liver cancer among ‘female cleaning service workers’ [27l as well as ‘female laundry and dry-cleaning workers’ 1281. Whereas trichloroethylene used to be applied only in industry and the exposure there appears to have been well controlled in many countries [291, the use of tetrachloroethylene as a dry-cleaning agent is in closer contact with the general population. Accordingly, reports are appearing to show that the exposure of not only the working population but the general population in the vicinity of dry-cleaning facilities is sometimes in excess of the occupational exposure limit [301. Well water pollution, possibly by a dry-cleaning factory, has been reported. Tetrachloroethylene concentrations in blood samples obtained from inhabitants downstream ranged up to 5 l&l and correlated significantly with tetrachloroethylene concentration in well water they regularly consumed [311. A large-scale study in 1982 on well water quality in Japan showed that both solvents together with methylchloroform were present in some samples

198

of well water at levels in excess of drinking water criteria. Follow-up studies in succeeding years showed that the excess rates reached the maximum probably in 1986-1987, followed by a gradual decrease thereafter (Table VI; 1321). A similar study of general air also confirmed the, presence of trichloroethylene and tetrachloroethylene (Table VII; [331). The levels may be increasing, but it is still difficult to estimate chronological changes because of the short span of the study. Tentative calculations with the results suggest that respiration as a route of entry to human body cannot be ignored, in contrast to the case of pollutant metals such as cadmium and lead for which the dietary intake is a predominant route 1341. TABLE VI DETECTION OF TRICHLOROETHYLENE(TRI), TETRACHLOROETHYLENE METHYLCHLOROFORM (MC) IN WELL WATER IN JAPAN Year

No. of well water studied

(TET) AND

In excess of criteriaa TRI

TET

MC

1982

1366

2.9

3.9

1984

< 5400

2.1

3.2

0.1

1985

< 3400

3.6

4.0

0.2

1986

< 2700

5.2

3.9

0.1

1987

< 3700

2.9

4.8

0.2

1988

0.1-6.9)

2.2 (0.2-9.3)

1989/1988 ratio

1.2

1.4

‘Average of determinations at 5 sites (range in parentheses). Cited from 1331.

199 HEALTH EFFECTS DUE TO DEPLETION OF OZONE LAYER BY SOME ORGANIC SOLVENTS

Chlorofluorocarbons (CFC) enjoyed wide-spread use until recent years as aerosol propellants, refrigerants, plastics foaming agents as well as degreasing solvents. In the Montreal Protocol 1351,however, it was recognized that world-wide emission of certain chemicals can deplete the ozone layer in a manner that is likely to result in adverse effects on human health and the environment. In this connection the phase out of fully halogenated CFC was required. Methylchloroform and carbon tetrachloride are also included. More than 90% of the atmospheric ozone is in the stratosphere. The latest report [361 states that significant global scale decrease in ozone has occurred over the years 1979-1989. With the depletion of the ozone layer, the atmosphere becomes more transparent to solar UV radiation. The UV radiation in a wavelength range of 280-315 nm is more hazardous to health. The biologically active UV radiation is measured in terms of DNA-damage weighted dose. Taking this unit, the increase in UV during the decade was estimated to be about 5% at 30” north latitude and about 10% in the polar region of the northern hemisphere whereas it was 5% at 3O”S, 15% at 55”S, and 40% at 85”s in the southern hemisphere. As for the health implication of such changes, the report 1351identifies the end-points as summarized in Table VIII. The table lists not only direct effects on human health such as ocular damage, increase in infectious diseases and skin cancer, but indirect effects on agriculture and fisheries, as well as increase in CO2 in the atmosphere. These areas (except for ocular damage) are, at the same time, noted in the report as the key areas of uncertainty. TABLEVIII HEALTHIMPLICATION OF STRATOSPHERIC OZONEDEPLETION Effectson

Remarks

Human health Ocular damage

Cataract, damage to the anterior lens capsule and presbyopia

Increase in infectious diseases

By activation of viruses and suppression of immune system

Cancer induction

Melanoma and other skin cancer

Terrestrial plants

Effects on agriculture, forestry and natural ecosystems

Aquatic ecosystem

Loss in phytoplankton which affects food web, the role of sea as a CO2 sink, etc. Changes in Nz-fixing microorganisms affecting e.g. rice production

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