Introduction

The chapters in this book contain an overview of the toxicity of a number of individual solvents or, in the case of glycol ethers and their acetates, a group of solvents. The emphasis is on occupational exposure, although not exclusively so, as examples and information are drawn from other areas. Definitions of some of the terms used are given in the glossary. Each chapter has the same layout, with information under the following headings.

SUMMARY

This includes a brief outline of the main features and risks of the chemical described.

DESCRIPTION

This section outlines the physical and chemical properties and lists the synonyms and identification numbers (CAS, UN, RTECS, EINECS) of the chemical or chemicals described in the chapter. These properties can influence the toxicity of a chemical. Odour thresholds (the lowest concentration of a vapour or a gas in air that can be detected by odour) are also included, but reported odour thresholds may vary widely. Where this is the case all the figures are quoted with the relevant reference. Several lists of odour thresholds for a number of chemicals have been published (e.g., Amoore and Hautala, 1983; Ruth, 1986).

OCCUPATIONAL EXPOSURE

Exposure limits

Exposure limits are set as the concentration in air of a chemical in the workplace that is thought to be safe. This means that most workers can be exposed at the given concentration or lower without harmful effects. These limits are intended for use as guidelines or recommendations in the control of potential workplace health hazards.

There are several different types of exposure limit. For most of the chemicals described here, the UK and USA time-weighted averages (TWA) are listed. The TWA is the concentration that could be tolerated by an average worker for a 40 hour working week (8 hours a day, 5 days a week). UK limits are quoted from EH40/2000, an annual list of occupational exposure limits published by the Health and Safety Executive (HSE). The American limits quoted are those set by the American Conference of Governmental Industrial Hygienists (ACGIH) in their publication Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Limits. Many countries produce their own lists of occupational exposure limits and an extensive list of international standards and exposure limits is given in the Appendix of Patty's Toxicology (Bingham et al., 2001).

Some exposure limits are also given a skin notation because of the risk of dermal absorption in addition to inhalation. This designation does not include substances that can cause dermal irritation, and it should be noted that absorption may be greater through damaged skin.

Toxicology of Solvents Biomonitoring

Biomonitoring is used to measure individual exposure to a chemical in addition to air sampling. It involves measurement of the concentration of a chemical determinant in the expired air, blood or urine of exposed workers. The determinant may be the chemical itself, a metabolite or a reversible biochemical change induced by the chemical. The biological exposure index (BEI) generally indicates a concentration of the chemical determinant below which nearly all workers should not experience adverse health effects. They are guidance values for assessing biological monitoring results and apply to 8 hour exposures over a 5 day working week.

BEIs usually represent concentrations which are most likely to be observed in healthy workers exposed to chemicals to the same extent as workers with inhalation exposure at the threshold limit value (TLV). A TLV is a term used by the ACGIH to express the airborne concentration of a material to which nearly all workers can be exposed day after day without adverse effects.

Undue weight should not be placed on a single evaluation of a BEI because of the variability of biological specimens. However, removal from exposure pending further investigation may be considered following a single determination if significant exposure is thought to have occurred. If measurements from a worker persistently exceed the BEI, investigation and action is recommended to reduce exposure. Investigation is also warranted where the BEIs of a group of subjects working in the same area and/or same shift exceed the designated concentration. In addition, samples below the BEI do not necessarily indicate the absence of risk to health (ACGIH, 2000).

BEIs are not intended to be used as a measure of adverse effects or a diagnosis of occupational illness, but they can be used to detect and determine dermal or gastrointestinal absorption in addition to inhalation exposure, to assess body burden, to determine past exposure in the absence of other means, to detect non-occupational exposure in workers, to test the effectiveness of personal protective equipment and engineering controls and to monitor work practices (ACGIH, 2000).

Various notations are included in the ACGIH BEIs. These are as follows:

• B (background) - The determinant may be present in samples from individuals who have not been occupationally exposed. Consequently, this may affect interpretation of the result and these background concentrations are incorporated in the BEI value.

• Nq (non-quantitative) - Biological monitoring should be considered for this chemical but due to insufficient data a specific BEI could not be determined.

• Ns (non-specific) - The determinant is non-specific for a single chemical as it may be detected following exposure to other chemicals.

• Sq (semi-quantitative) - The determinant is an indicator of exposure but the quantitative interpretation is ambiguous. The determinant may be used as a screening test if a quantitative test is impractical, or as a confirmatory test where the quantitative test is non-specific and the origin of the determinant is in question.

TOXICITY

The individual risk from a particular chemical is determined by a number of factors including the route of exposure, dose, duration of exposure, work environment (e.g., temperature, humidity, hygiene practices) and individual factors of the victim (e.g., genetic factors, body mass, age, gender, pre-existing disease, concurrent exposure, correct use of protective equipment) and the chemical (physical and chemical properties). Toxicokinetics including the absorption, distribution, metabolism and elimination of a chemical also influence toxicity (IPCS, 2000). For many chemicals, for example benzene, hexane and dimethylformamide (DMF), it is not the chemical itself but one or more metabolites that are known or thought to be responsible for its toxic effects. In these cases, toxicity may therefore be influenced more by the extent of metabolism rather than the dose.

A solvent may also vary in its constituents and contaminants, and these can also influence toxicity. In some cases investigators have not been specific about the solvent they are studying. For example, white spirit may contain aromatic as well as aliphatic compounds, and these are not always specified; xylenes are available in three isomers or as a mixture and it is not always stated which is under investigation. Toxicity information, particularly in the older literature may relate to contaminants rather than the solvent of interest. This is the case with toluene and xylenes, where the haematological effects reported were probably due to benzene contamination.

Where it has been possible information on human exposure has been used. In some cases this information is lacking and data on animal toxicity has been used although this has its limitations, for example species differences in body size, metabolism, dosing, toxicokinetics, and susceptibility (IPCS, 1999). Information from experimental animals has also been used to support findings from human studies.

Many toxicity studies have limitations involving small sample size, lack of appropriate controls, lack of measurement of exposure concentrations and non-exclusion of confounding factors. These problems have been highlighted where appropriate. Studies on occupational exposure to chemicals are further complicated by the fact that in many situations workers are exposed to a number of different substances and in many cases the effects of an individual solvent cannot be determined.

Mode of action

This section outlines the known and suggested mechanisms of toxicity of the solvents. However, for many of the chemicals described the mode of action has not been fully established and information is limited. In contrast, for some solvents, such as benzene, there is a large quantity of literature on the possible mechanisms of action that are multifactorial and complex.

Metabolic interactions

Many different solvents are metabolised by the same metabolic pathways and consequently may interact with each other. Co-exposure to other substances including tobacco smoke, ethanol or pharmaceuticals can also affect the toxicokinetics or toxicity of a solvent. In some cases the solvent itself may be of relatively low toxicity but can increase the toxicity of other substances. The classic example of this is methyl ethyl ketone (MEK), which can potentiate the toxicity of other substances, making them more hazardous at a lower concentration. In this section studies investigating the extent and possible hazards of metabolic interactions are outlined and each substance is discussed separately. Studies reporting no metabolic interaction are also included.

CASE REPORTS

Case reports are included to provide an overview of poisoning from the solvents discussed. The emphasis is on accidental exposure in the workplace and the case reports serve to demonstrate the variable clinical picture that can result and the circumstances in which poisoning can occur. These include exposure due to faulty equipment, spills, leaks and fires, incorrect use of protective equipment, intentional abuse, formulation changes, lack of knowledge of the risks involved and failure of industrial hygiene practices.

CLINICAL EFFECTS

This section is divided into acute and chronic exposure and details the clinical effects by route of exposure (inhalation, dermal, eye and ingestion). In the industrial situation inhalation is the most common route of exposure (Proctor, 1996; Harbison, 1998) and ingestion is uncommon. However, it is included here for the sake of completeness and because of the potential for accidental or intentional ingestion. For some of the chemicals described, such as methanol, severe poisoning is most likely from ingestion rather than any other route of exposure, and the majority of the information on the toxicity of the chemical is derived from cases of intentional ingestion. Where similar clinical features can occur from more than one route of exposure, particularly ingestion and inhalation, these effects are described under the heading of systemic effects, to avoid repetition.

In some instances (e.g., toluene, trichloroethane) much of the information on clinical effects in the literature relates to solvent abuse. Whereas exposure in the industrial setting usually involves chronic low level exposure, abuse is usually intermittent inhalation of a very high (often unmeasured) concentration. However, we have tried to make it clear in these chapters what aspect of toxicology is being discussed.

Carcinogenicity

For most of the solvents discussed there is only relatively limited information on the risks of cancer. The exception is benzene. One group of workers exposed to benzene have been the subject of numerous studies and they are the most intensively studied group in occupational epidemiology (Paustenbach et al., 1992). For the other solvents most information derives from a small number of case reports and case series. Carcinogenicity is often difficult to evaluate in human populations because of the long lag time between exposure and onset. This makes it particularly difficult to correlate dose to effect, and there are also numerous confounding effects including exposure to other chemicals, socioeconomic factors, alcohol intake and smoking habits that further complicate the picture.

The International Agency for Research on Cancer (IARC), part of the World Health Organization (WHO), publishes authoritative independent assessments by international experts of the carcinogenic risks posed to humans by a variety of agents, mixtures and exposures. The evidence is evaluated from human and experimental animal data and the substance or exposure is categorised. The categories reflect the strength of the evidence derived from these studies and other relevant data. The IARC categories (IARC, 2001) have been stated for the chemicals described, where available. They are defined as follows:

• Group 1: The agent is carcinogenic to humans. The exposure circumstance entails exposures that are carcinogenic to humans.

This category is used when there is sufficient evidence of carcinogenicity in humans. Exceptionally, an agent may be placed in this category when evidence of carcinogenicity in humans is less than sufficient but there is sufficient evidence of carcinogenicity in experimental animals and strong evidence in exposed humans that the agent acts through a relevant mechanism of carcinogenicity.

This category includes agents, mixtures and exposure circumstances for which, at one extreme, the degree of evidence of carcinogenicity in humans is almost sufficient, as well as those for which, at the other extreme, there are no human data but for which there is evidence of carcinogenicity in experimental animals. Agents, mixtures and exposure circumstances are assigned to either group 2A (probably carcinogenic to humans) or group 2B (possibly carcinogenic to humans) on the basis of epidemiological and experimental evidence of carcinogenicity and other relevant data.

• Group 2A: The agent is probably carcinogenic to humans. The exposure circumstance entails exposures that are probably carcinogenic to humans.

This category is used when there is limited evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in experimental animals. In some cases, an agent may be classified in this category when there is inadequate evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in experimental animals and strong evidence that the carcinogenesis is mediated by a mechanism that also operates in humans. Exceptionally, an agent, mixture or exposure circumstance may be classified in this category solely on the basis of limited evidence of carcinogenicity in humans.

• Group 2B: The agent is possibly carcinogenic to humans. The exposure circumstance entails exposures that are possibly carcinogenic to humans.

This category is used for agents, mixtures and exposure circumstances for which there is limited evidence of carcinogenicity in humans and less than sufficient evidence of carcinogenicity in experimental animals. It may also be used when there is inadequate evidence of carcinogenicity in humans but there is sufficient evidence of carcinogenicity in experimental animals. In some instances, an agent, mixture or exposure circumstance for which there is inadequate evidence of carcinogenicity in humans but limited evidence of carcinogenicity in experimental animals together with supporting evidence from other relevant data may be placed in this group.

• Group 3: The agent is not classifiable as to its carcinogenicity to humans.

This category is used most commonly for agents, mixtures and exposure circumstances for which the evidence of carcinogenicity is inadequate in humans and inadequate or limited in experimental animals. Exceptionally, agents for which the evidence of carcinogenicity is inadequate in humans but sufficient in experimental animals may be placed in this category when there is strong evidence that the mechanism of carcinogenicity in experimental animals does not operate in humans. Agents, mixtures and exposure circumstances that do not fall into any other group are also placed in this category.

• Group 4: The agent is probably not carcinogenic to humans.

This category is used for agents or mixtures for which there is evidence suggesting lack of carcinogenicity in humans and in experimental animals. In some instances, agents or mixtures for which there is inadequate evidence of carcinogenicity in humans but evidence suggesting lack of carcinogenicity in experimental animals, consistently and strongly supported by a broad range of other relevant data, may be classified in this group.

The evidence relevant to carcinogenicity from studies in humans (that is, the terms in italics in the above descriptions of the IARC categories) are defined as follows (IARC, 2001):

• Sufficient evidence of carcinogenicity: The Working Group considers that a causal relationship has been established between exposure to the agent, mixture or exposure circumstance and human cancer. That is, a positive relationship has been observed between the exposure and cancer in studies in which chance, bias and confounding factors could be ruled out with reasonable confidence.

• Limited evidence of carcinogenicity: A positive association has been observed between exposure to the agent, mixture or exposure circumstance and cancer for which a causal interpretation is considered by the Working Group to be credible, but chance, bias or confounding factors could not be ruled out with reasonable confidence.

• Inadequate evidence of carcinogenicity: The available studies are of insufficient quality, consistency or statistical power to permit a conclusion regarding the presence or absence of a causal association between exposure and cancer, or no data on cancer in humans are available.

• Evidence suggesting lack of carcinogenicity: There are several adequate studies covering the full range of levels of exposure that humans are known to encounter, which are mutually consistent in not showing a positive association between exposure to the agent, mixture or exposure circumstance and any studied cancer at any observed level of exposure. A conclusion of 'evidence suggesting lack of carcinogenicity' is inevitably limited to the cancer sites, conditions and levels of exposure and length of observation covered by the available studies. In addition, the possibility of a very small risk at the levels of exposure studied can never be excluded.

The evidence relevant to carcinogenicity in experimental animals is defined separately and classified into one of the following categories (IARC, 2001):

• Sufficient evidence of carcinogenicity: The Working Group considers that a causal relationship has been established between the agent or mixture and an increased incidence of malignant neoplasms, or of an appropriate combination of benign and malignant neoplasms in (a) two or more species of animals or (b) in two or more independent studies in one species carried out at different times or in different laboratories or under different protocols. Exceptionally, a single study in one species might be considered to provide sufficient evidence of carcinogenicity when malignant neoplasms occur to an unusual degree with regard to incidence, site, tumour type or age at onset.

• Limited evidence of carcinogenicity: The data suggest a carcinogenic effect but are limited for making a definitive evaluation because, for example, (a) the evidence of carcinogenicity is restricted to a single experiment; or (b) there are unresolved questions regarding the adequacy of the design, conduct or interpretation of the study; or (c) the agent or mixture increases the incidence only of benign neoplasms or lesions of uncertain neoplastic potential, or of certain neoplasms which may occur spontaneously in high incidences in certain strains.

• Inadequate evidence of carcinogenicity: The studies cannot be interpreted as showing either the presence or absence of a carcinogenic effect because of major qualitative or quantitative limitations, or no data on cancer in experimental animals are available.

• Evidence suggesting lack of carcinogenicity: Adequate studies involving at least two species are available which show that, within the limits of the tests used, the agent or mixture is not carcinogenic. A conclusion of evidence suggesting lack of carcinogenicity is inevitably limited to the species, tumour sites and levels of exposure studied.

Genotoxicity

There are many different types of tests for evaluation of the genotoxic properties of chemicals including tests involving bacteria (usually Salmonella typhimurium), yeast (Saccaromyces cerevisiae), fruit flies (Drosophila melanogaster), cultured mammalian cells and experimental animals (Carere et al., 1995). These data have not been evaluated here and only summary information is given. However, information from studies involving exposed workers has been used.

Reproductive toxicity

This section discusses toxicity affecting the reproductive system, including effects on males and females, and the embryo and fetus during pregnancy. In most cases data on humans are lacking or inconclusive and animal data is discussed. However, in many studies the animals are exposed to high doses, sometimes for prolonged periods, and this does not reflect the industrial situation. Consequently, these studies must be interpreted with caution.

RISK GROUPS

Some individuals may be more at risk of adverse health effects following exposure to a particular chemical. This may be due to a variety of factors including body mass, pre-existing disease, gender, age, ethnic differences and genetically determined variation in enzyme activities. The risk groups for a particular chemical are outlined in this section, but in many cases specific studies investigating these confounding factors are lacking.

HOSPITAL MANAGEMENT

Treatment is outlined only briefly and is intended as a guide only; expert advice should always be sought, for example from a poisons information service.

The management of most cases of poisoning is symptomatic and supportive. Gastric decontamination with activated charcoal or gastric lavage is usually only worthwhile within one hour of ingestion (AACT/EAPCCT, 1997a,b). Activated charcoal is made from organic material such as coconut shells, peat or wood that has been burned and then heated to a very high temperature in steam, air or carbon dioxide. The result is a finely divided powder with an extensive pore structure and a large surface area (1,000 m2/g) that can adsorb a wide range of substances. A substance adsorbed by charcoal is less available to be absorbed systemically, rather, it is carried through the gastrointestinal tract and excreted. However, activated charcoal is unlikely to be of benefit with most solvents because they are not adsorbed, and activated charcoal will therefore be ineffective in reducing absorption from the gastrointestinal tract. Administration of activated charcoal may sometimes result in vomiting and this may increase the risk if the solvent is an aspiration hazard, because of the possibility of pulmonary damage if the chemical enters the lungs. Similarly, where gastric lavage is undertaken, and it will usually only be necessary following an intentional ingestion, the airway must be protected if the solvent is an aspiration hazard.

A small number of substances have specific antidotes and these have been discussed briefly in the appropriate chapters. Treatment of chronic exposure is outlined briefly and in most cases is symptomatic and supportive.

FURTHER INFORMATION

Numerous organisations including those listed here, publish documents on aspects of chemical toxicity and testing, including monographs on specific chemicals.

• The Environmental Health Criteria (EHC) Series

The Concise International Chemical Assessment (CICAD) Series

These documents are published under joint sponsorship of the UN Environmental Programme, the International Labour Organization and the World Health Organization and within the framework of the Inter-Organization Programme for the Sound Management of Chemicals. Further information is available from: Marketing and Dissemination, World Health Organization, 1211 Geneva 27, Switzerland. Website www.who.int/pcs/index.htm

• Toxicological Profiles from the Agency for Toxic Substances and Disease Registry (ATSDR)

Further information is available from: The Agency for Toxic Substances and Disease Registry, Division of Toxicology/Toxicology Information Branch, 1600 Clifton Road NE, E-29, Atlanta, Georgia 30333, USA. Website www.atsdr.cdc.gov

• European Centre for Ecotoxicology and Toxicology of Chemicals

Several different types of publication are available including Joint Assessment of Commodity Chemicals (JACC) Reports, Technical Reports (TR) and monographs. Further information is available from: ECETOC, 4 Avenue E. Van Nieuwenhuyse (Bte 6), B-1160 Brussels, Belgium. Website www.ecetoc.org

REFERENCES

ACGIH. 2000 Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Limits. American Conference of Governmental Industrial Hygienists.

AACT/EAPCCT. 1997a American Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicologists. Position statement: gastric lavage. Clin Toxicol 35 (7):711-719.

AACT/EAPCCT. 1997b American Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicologists. Position statement: single-dose activated charcoal. Clin Toxicol 35 (7):721-741.

Amoore JE, Hautala E. 1983 Odor as an aid to chemical safety: odor thresholds compared with threshold limit values and volatilities for 214 industrial chemicals in air and water dilution. J Appl Toxicol 3 (6):272-290.

Bingham E, Cohrssen B, Powell CH (editors). 2001 Appendix: United States and international standards. In: Patty's Toxicology, fifth edition, Volume 8. John Wiley & Sons Inc., New York, pp. 1103-1326.

Carere A, Mohn GR, Parry JM, Sors AI, Nolan CV. 1995 Methods and Testing Strategies for Evaluating the Genotoxic Properties of Chemicals. European Commission Report EUR 15945 EN.

EH40/2000. Occupational Exposure Limits. Health and Safety Executive, TSO, London.

Harbison RD. 1998 Diagnosis of occupational disease. In: Hamilton & Hardy's Industrial Toxicology, fifth edition. RD Harbison (editor). Mosby, St Louis.

IARC. 2001 International Agency for Research on Cancer website at www.iarc.fr.

IPCS. 1999 Environmental Health Criteria 210. Principles for the Assessment of Risks to Human Health from Exposure to Chemicals. International Programme on Chemical Safety, World Health Organization, Geneva.

IPCS. 2000 Environmental Health Criteria 214. Human Exposure Assessment. International Programme on Chemical Safety, World Health Organization, Geneva.

Paustenbach DJ, Price PS, Ollison W, Blank C, Jernigan JD, Bass RD, Peterson HD. 1992 Reevaluation of benzene exposure for the pliofilm (rubberworker) cohort (1936-1976). J Toxicol Environ Health 36:177-231.

Proctor NH. 1996 Toxicologic concepts - setting exposure limits. In: Proctor and Hughes' Chemical Hazards of the Workplace, fourth edition. Hathaway GJ, Proctor NH, Hughes JP (editors). John Wiley & Sons Inc., New York.

Ruth JH. 1986 Odor threshold and irritation levels of several chemical substances: a review. Am Ind Hyg Assoc J 47:A142-A151.

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