This chapter addresses airborne exposure potential in detail, due to the volatile nature of many solvents. However, as noted, solvent exposure is possible by multiple routes. For example, in situations where groundwater with solvent contamination is used for household purposes, there is the possibility of ingestion from drinking the water, dermal exposure from bathing activities, and inhalation related to volatilized solvents during clothes washing, showering, cooking, and other chores. Similarly, in industrial operations that employ solvents, joint exposure may occur due to splashes onto the skin, inhalation of vapors in work areas, and hand-to-mouth transfer of the chemicals during eating, smoking, or other common activities. Recognition of these multiple potential pathways has led to workplace requirements involving respiratory protection and hygiene practices limiting exposure possibilities. Differences in absorption, and other route-specific considerations for solvents, are further addressed in Section 18.3.

Not only is it important to address potential exposures to individual solvent agents but also possible interactive effects of multiple exposures, since these are the rule, rather than the exception. Assessment of the magnitude of exposure is often complex and may require detailed evaluation of inhalation and/or dermal contact, as well as estimates of exposure frequency and duration. Some common volatile organic chemical (VOC) solvents that may be encountered indoors and outdoors include benzene, toluene, xylenes, alcohols, trichloroethylene (trichloroethene, TCE), and formaldehyde. Exposure to organic solvents and their constituents can occur for individuals who live near industrial facilities that presently use or have used these solvents, as well as in the home. Many solvents are found in groundwater, soils, air, and other environmental media near National Priorities List (NPL) sites that are managed under Superfund (Comprehensive Environmental Response, Compensation, and Liability Act, aka CERCLA). Much of this is related to past storage, handling, and disposal practices at numerous industrial facilities. As of September 2014, there were over 1300 listed NPL sites and another 51 proposed sites in the United States, many of which are significant for the presence of variable solvent contamination profiles in soils and groundwater.

Industrial Exposures

There have been extensive advances in worker protection standards in the United States; however, industrial solvent exposures remain of global health interest for workers, many of whom are unfamiliar with potential hazards associated with exposures. The Occupational Safety and Health Administration (OSHA) has concluded that millions of U.S. workers are exposed to solvents in varying degrees on a daily basis. In some professions (e.g., painters), nearly all workers may have some degree of exposure, though education and protective measures (e.g., ventilation, spraybooths, respirators), coupled with introduction of water-based paints and adhesives, have reduced such exposure. Japan reports that smaller industries use nearly five times as much solvent volume compared to large enterprises, and they have experienced shifts in solvent use from aromatics to alcohols.

Exposures to organic solvents in an occupational setting also may occur in research laboratories, hospitals, and dry cleaners. In histology labs, formaldehyde (preservative) and xylenes (clearing agents) are the most common chemicals used and historically have been associated with pulmonary damage. Recently, housekeeping practices in the healthcare industry, which employ solvent-based cleaning products, have been identified as an occupational risk due to the asthma-like symptoms and dermatitis reported by some workers.

A limited epidemiologic database suggests that exposure to solvents and volatile chemicals in service station workers may be associated with restrictive airway disease, but demonstration of persistent lung complications has been inconsistent. A relationship also has been postulated for exposure to some chlorinated solvents during automotive degreasing work and an increase in risk of non-Hodgkin’s lymphoma (NHL); however, that literature also is inconsistent. Ubiquity of solvents in industry, and potential for concurrent or sequential exposure to multiple chemicals, complicates the distinction between chemical causation of adverse effects and simple association of adverse effects with exposure in time and place. Relationships between simple association and chemical causation are discussed elsewhere in this book (see Chapter 21).

Industrial practices that result in the evaporative loss of volatile solvents (e.g., metal degreasing, application of surface coatings, chemical separations) are of particular interest in an exposure context. Protective equipment, engineering controls, and work practices can be effective in limiting exposures, but careless or inexperienced handling of solvents may still occur in small facilities (e.g., automobile service and repair, metal fabricators) and during activities in large and otherwise well-run factories and service industries. Methods used for worker exposure characterization and quantification are discussed elsewhere in this book (see Chapter 22). Solvent exposure potential varies among individuals, as well as over time for a specific individual, based on job type, workplace duties, and schedule. Within possible occupational exposure groups, it is important to consider sensitive individuals and populations when evaluating exposure and risk, including those with preexisting health conditions such as weakness of the immune system.

Occupational airborne guidelines that are designed to control exposures to solvents and other materials in the workplace may be expressed in units of volume/volume (e.g., parts per million (ppm)), as well as units of mass/volume (e.g., mg per cubic meter (mg/m³)). For vapors and gases, these data if expressed in either form may be interconverted according to the following expressions:

where

Rearranging this expression provides an opportunity to convert airborne concentrations that are expressed with different units in the other direction as well, as follows:

For dose estimates, units of mg/m³ are useful in conjunction with inhalation rates (units of m³/h or m³/day) to determine chemical intake in risk calculations. These unit conversion relationships do not apply for dusts, aerosols, and other nongaseous forms.

Household and Other Exposures

As noted, in addition to what are considered conventional industrial exposures, potential exposures to household products containing solvents and nonoccupational handling of petroleum products remain significant sources of exposure to hydrocarbon solvents. Residential exposure by all routes can occur when practicing hobbies (e.g., paints, thinners, adhesives), conducting home repairs (e.g., paints varnishes, thinners), using household cleaning products (alcohols, ethers, floor strippers, tub/tile cleaners), using fuels in lawn equipment (gasoline, diesel), and during recreational abuse of volatile inhalants, known as “huffing,” in which a variety of solvents and pressurizing agents are used to attain intoxication-related euphoria, delusions, sedation, and hallucinations. Chronic inhalant abuse may lead to adverse neurologic conditions.

Absorption, Distribution, Metabolism, and Excretion

As noted, solvent exposure may occur via oral, dermal, and inhalation routes, as well as a combination of these. Absorption can occur from direct liquid contact, and abraded or cut skin may enhance dermal absorption. While dermal penetration of solvents typically is negligible at low air concentrations, the ACGIH and OSHA note that this route for some substances may be significant at high air concentrations, hence an occupational “skin” designation, applicable in confined spaces or areas where respiratory protection (e.g., use of air-purifying or air-supplied respirators) limits potential for inhalation. For example, exposure to 2-butoxyethanol vapor may cause dermal uptake that exceeds inhalation. Solvent absorption by the lungs is dependent on several factors, including air concentration, as well as ventilation rate, depth of respiration, and pulmonary circulation, all of which are influenced by workload.

Once absorbed, solvents may be transported to other areas of the body, including organs where biotransformation may occur, resulting in formation of metabolites. Significant route-specific differences exist between uptake and the potential for adverse effects from solvents. Intake via the oral and dermal routes causes absorption into the venous circulation, which allows what is known as “first-pass” degradation or clearance by enzymatic process of the liver. Inhalation intake results in absorption via the alveoli into the arterial circulation, which distributes absorbed solvents to various locations prior to hepatic metabolism. For this reason, as well as the fact that airborne concentrations may be quite high in some cases, the inhalation route often is of greater toxicological concern on a strict numerical dose comparison.

Many volatile solvents can be eliminated either as the parent compound or in metabolized form in exhaled breath, varying with workload. This can be independent of exposure route and is the basis for sampling expired air as a measure of occupational exposure (see Table 18.3). Less water-soluble substances (e.g., chlorinated solvents) may penetrate more deeply into the lungs.

Given heterogeneity among solvents, numerous potential metabolic pathways exist, as described elsewhere in this book. The P450 enzyme system and the glutathione pathways often are involved, catalyzing oxidative reactions and conjugation to form water-soluble substances excretable in urine or bile. Several pathways may exist for the biotransformation of a specific solvent, depending on exposure route and concentration. Excretion of metabolites (e.g., s-phenylmercapturic acid from benzene, trichloroacetic acid from TCE, mandelic acid from styrene) forms the basis for biological monitoring programs in exposure characterization. Although the liver is the primary site of metabolism, other organs (e.g., kidney, lung) exhibit biotransformation capacity as well. Formation and accumulation of metabolites can occur if initial steps of biotransformation are present, but not later steps. For example, aldehydes may be metabolized readily in the liver, while the same aldehyde may accumulate in the lung and cause pulmonary damage due to limited aldehyde dehydrogenase. Beyond generally beneficial aspects of biotransformation (i.e., detoxification) and excretion, solvent metabolism occasionally may generate products that are more toxic than the parent compound. Such metabolic “activation,” also termed “bioactivation,” and resultant reactive intermediates (e.g., epoxides and radicals) are considered responsible for some toxic effects of solvents, especially with chronic exposure. This is illustrated by TCE, which exhibits variable metabolism in some rodents with dose, and that metabolism may produce novel toxicity elsewhere.

Metabolic enzymes may be increased in activity (“induced”) by previous or concomitant chemical exposures, such as therapeutic drugs, foods, alcohol, cigarette smoke, and industrial exposures. Competitive interactions, which may affect enzyme activity for solvents in industrial scenarios, also may influence toxicity, such that exposure to multiple chemicals is not always worse than individual exposures (e.g., toluene inhibits benzene metabolism and toxicity). Saturation of normal metabolic degradation pathways may cause qualitative shifts in metabolism to other pathways. While a normal pathway may cause detoxification, saturation or overwhelming of the pathway may cause “shunting” to activation pathways (e.g., 1,1,1-trichloroethane, n-hexane, perchloroethylene (PERC), and 1,1-dichloroethene).

Partition coefficients (Kp) for air–blood, fat–blood, and brain–blood can be calculated and used to describe differential solvent behavior in various tissues. Such values are useful to understand the preferential uptake and storage of solvents and to explain greater sensitivity of some organs to adverse effects.

Acute versus Chronic Effects

As discussed subsequently in greater detail by chemical class, solvents can have both acute, short-term effects based upon one or a few high-level exposures (e.g., irritation, neurological effects) and chronic effects that may be expressed in delayed fashion following prolonged exposures at lower levels (e.g., kidney disease, liver injury, cancer). Acute effects typically result from the rapid overwhelming of existing detoxification and excretion mechanisms, and they may be transient/reversible. Chronic effects often are related to repetitive, unrepaired, low-level damage that is accumulative over lengthy periods of exposure, and these effects are less likely to be reversible. The intermediate case, where more frequent or regular high-level exposures may occur, is difficult to predict, given individual sensitivities and resilience.

For some solvents (e.g., aldehydes, ketones), the ability to detect odor or irritation at low air concentrations is a useful characteristic that can act as an “early warning” tool against acute and chronic exposure potential. However, for most industrially and environmentally important solvents (e.g., benzene, chlorohydrocarbons), odor does not serve as a sufficient warning property, and significant exposures can occur before they are detectable by smell. Avoidance of such exposure circumstances is a foundation of occupational and environmental monitoring programs.

Central Nervous System Effects

A common physiological effect associated with short- or long-term, high-level exposure to some organic solvents is depression of central nervous system (CNS) activity, causing general anesthesia, decreased brain/spinal cord activity, and lowered sensitivity to external stimuli, with unconsciousness or death as the severest consequence. Many solvents are lipophilic (“fat loving”), a feature typically coupled with a low affinity for water (hydrophobic). Those compounds tend to accumulate in lipid-rich areas, including blood, brain, and depot (storage) fats. Accumulation in or direct damage to nerve cells can disrupt normal nerve excitability and adversely affect nerve impulse conduction. While organic solvents with few or no functional groups generally are lipophilic and exhibit some limited degree of CNS-depressant activity, this property generally increases with carbon chain length. Changes in toxicity are most evident when larger functional groups are added to small organic compounds, since the increase in molecular size generally decreases water solubility and increases lipophilicity. In practical terms, this applies only to chemicals up to carbon chain length of about six. As molecular size increases beyond this point for a functional class (e.g., amines, alcohols, ethers), vapor pressure decreases and exposure issues (e.g., inhalation) decrease dramatically.

Unsaturated chemicals (i.e., where hydrogens have been lost, forming double or triple bonds between carbon atoms) typically are more potent CNS-depressant chemicals than their saturated (i.e., single bond) counterparts. Similarly, CNS-depressant properties of organic solvents generally are enhanced by an increasing extent of halogenation (e.g., chlorine, bromine) and, to a lesser extent, by addition of alcohol (OH) groups. For example, while methane and ethane are gases, are not anesthetics, and act as simple asphyxiants at high concentrations, both of the corresponding alcohol analogs (i.e., methanol and ethanol) are liquids and are potent CNS depressants. Methylene chloride has anesthetic properties, but chloroform (CHCL₃) is more potent than methylene chloride, and carbon tetrachloride (CCL₄) is the most potent anesthetic of the group.

Toluene encephalopathy has been reported in high-level inhalant abuse, characterized by severe neurotoxicity. Evidence is limited that such a syndrome occurs at low-level exposures and there is considerable doubt as to whether “solvent-induced chronic encephalopathy” exists in reasonable exposure circumstances. That syndrome, described in the late 1970s, was explored more fully in the 1980s, though recent reviews do not conclude that chronic low-level solvent exposure typically results in CNS or peripheral nervous system (PNS) injury.

To illustrate the nonspecificity of solvent neurotoxic effects, and related problems that may be faced by a health specialist in trying to diagnose poorly characterized exposure situations, the following constellations of symptoms are described for a few common agents. It should be noted that, in contrast to these acute effects, effects of chronic exposure to these agents may differ dramatically, as discussed elsewhere in the chapter:

• Benzene: euphoria, excitement, headache, vertigo, dizziness, nausea, vomiting, irritability, narcosis, coma, and death
  
• Carbon tetrachloride: conjunctivitis, headache, dizziness, nausea, vomiting, abdominal cramps, nervousness, narcosis, coma, and death
  
• Methanol: euphoria, conjunctivitis, decreased vision, headache, dizziness, nausea, vomiting, abdominal cramps, sweating, weakness, delirium, coma, and death

PNS Effects

The literature is clear that select organic solvents (e.g., n-hexane, methyl n-butyl ketone, carbon disulfide) can cause “distal axonal peripheral neuropathy,” also often termed “dying-back axonopathy” as defined by degradation of the axon or nerve cell body. It typically affects the feet and lower legs before the hands and may be partially reversible if identified sufficiently early in the process. The condition is associated with weakness, alteration or loss of sensation, impairment of reflexes, and eventual generalized muscle wasting. Occupational development of the condition has been reported in painters, automotive technicians, and workers in the shoe and furniture manufacturing sectors. Development of the condition is slow, though it may be accelerated in cases of inhalant abuse, and deterioration arguably may progress beyond the time at which exposure ceases, though the mechanism for such progression is not described. It is necessary to diagnose these disorders carefully while keeping in mind the possibility of other potential etiologies for the peripheral neurological observations (e.g., trauma, lead exposure, inflammation, diabetes, autoimmunity, heredity).

Renal and Hepatic Effects

Nephrotoxic effects have been associated with both acute and chronic exposures to halogenated hydrocarbons (e.g., chloroform, tetrachloroethylene). The primary target of chloroform is the proximal kidney tubule where metabolism via renal cellular P450 produces reactive intermediates that cause damage followed by protein and glucose leakage to the urine, as well as increased blood urea nitrogen (BUN) levels. PERC is one of a group of chemicals that cause serious sex-specific and species-specific α2-microglobulin nephropathy in animals. However, humans are not at risk of this particular nephropathy because we do not synthesize the α2-microglobulin protein. As described in subsequent sections, organic solvents known to damage the liver include ethanol and chlorinated hydrocarbons. Enzymes (e.g., P450) and other factors that affect solvent transformation play a role in determining the extent of hepatotoxicity associated with these and related chemicals. Factors that activate P450 increase toxicity of many chlorinated solvents, and those that inhibit (decrease) P450 activity tend to reduce toxicity. Coexposure to some alcohols and chlorinated solvents has been associated with exacerbation of toxicity compared with that expected from either agent alone.

Irritation of Tissues and Membranes

Cell membranes are composed principally of a protein–lipid matrix, and organic solvents may act to dissolve that matrix or extract the fat (lipid) portion from the membrane, causing membrane and tissue irritation. This “defatting” process, when applied to skin, causes drying, irritation, and cell damage. Injury to the lungs and eyes may be caused by similar processes. As described previously, addition of some functional groups to organic molecules predictably influences toxicological properties. For example, amines, organic acids, alcohols, aldehydes, and ketones may cause cell membrane damage by precipitation and denaturation of proteins following sufficient exposures.

As is true for CNS depression, irritation by unsaturated compounds generally is stronger than for the corresponding saturated analogs. As molecular size increases, irritant properties typically decrease, and solvent defatting action of the hydrocarbon portion is altered. Table 18.6 presents relative potency of selected functional groups regarding CNS-depressant effects and irritation. The rankings become less applicable as the larger, more complex, multisubstituted compounds are considered.

A number of solvents are inhalation irritants, though irritation often is restricted to the upper airways due to the high degree of water solubility of the substances and the tendency to dissolve in moisture of mucous membranes.

Cancer

As with toxicological evaluations of other potential solvent-related adverse effects, the complex nature of industrial exposure scenarios complicates the objective evaluation of malignancy attributed to a specific solvent. Thus, many occupational studies end up considering solvent exposure as a general “risk factor” for neoplasia but stop short of establishing “cause and effect” relationships. While in some occupational exposure circumstances it is possible to establish a causative element of human cancer risk for industrial activities (asbestos and mesothelioma in some shipyard employees; angiosarcoma in concentrated vinyl chloride exposure), such is not the case for most solvents. There is historical documentation for benzene as a human carcinogen under well-described intense exposure circumstances. Multiple factors may be responsible for the observed effects, but metabolism of benzene to one or more reactive metabolites (e.g., epoxides) is likely to be responsible for the myelotoxicity. A complementary hypothesis suggests that a depressant effect by benzene or its metabolites on cell-mediated immunity may influence the carcinogenic process. It is interesting that the substituted benzene analogs toluene and xylenes are noncarcinogenic, while styrene (or vinylbenzene) forms reactive metabolites, as does benzene, notably styrene oxide. Styrene recently was listed as reasonably anticipated to be a human carcinogen in the NTP 12th Report on Carcinogens. That listing was based on limited evidence in human studies, sufficient evidence in animals, and supporting data on carcinogenesis mechanisms.

Some chlorinated solvents, such as carbon tetrachloride, chloroform, tetrachloroethylene (PERC), TCE (trichloroethylene), and vinyl chloride, exhibit carcinogenic potential, notably hepatic tumors, in animals. Carcinogenic potential associated with TCE exposure has been of interest since the mid-1970s, when the National Cancer Institute (NCI) reported increases in liver cancer in male mice receiving TCE by gastric intubation. TCE, like some other chlorinated hydrocarbons, exhibits limited, inconsistent, and controversial mutagenic activity in bacterial test systems after microsomal activation, so the mutagenic effect is likely dependent on the products of metabolism, which has influenced recent interest in actual TCE potency. In the recent 2011 Toxicological Review, the U.S. EPA characterizes TCE as “carcinogenic to humans” based upon procedures outlined in the U.S. EPA 2005 Guidelines for Carcinogen Risk Assessment. That classification relies on evidence of a putative causal association between TCE exposure in humans and kidney cancer, in addition to carcinogenicity in the liver and lymphoid tissues. Other groups (e.g., ACGIH) continue to classify TCE as A2 (“suspected human carcinogen”), while the International Agency for Research on Cancer (IARC) considers TCE in class 2A “probably carcinogenic to humans.” PERC is considered “likely to be a human carcinogen by all routes of exposure” as published in the 2012 Toxicological Review released by the U.S. EPA.

Apart from leukemogenic effects associated with chronic benzene exposure, the literature available to document specific cancer hazards from exposure to organic solvents is inconsistent, though some epidemiological observations have been published regarding cancer and chlorinated solvent exposure. For example, Hodgkin’s lymphoma and NHL arguably have been linked to occupational exposure to some aliphatic, aromatic, and chlorinated solvents. Recently, a study of nearly 15,000 aircraft maintenance workers with exposure to TCE and other solvents reported a decrease in overall cancer mortality but a small excess in NHL, multiple myeloma, and bile duct cancer. The U.S. EPA inhalation unit risk and oral CSF for TCE were predicated partly on NHL risk.

Reproductive Effects

For most solvents, reproductive effects are not among the most sensitive measures of toxic effects. Reproductive toxicity has been reported following exposure to 2-methoxyethanol (2-ME), 2-ethoxyethanol (2EE), and n-hexane. 2-ME may damage the testes and cause infertility at extreme doses. It also has been shown to be teratogenic in animal studies, as has exposure to 2-bromopropane, carbon disulfide, and ethylene glycol monomethyl ether. Reproductive dysfunction was reported following exposure at high levels to toluene and other petrochemicals, though more sensitive measures of exposure occur at lower levels. Toluene abuse in pregnancy can lead to teratogenic effects labeled “fetal solvent syndrome.” Organic solvent exposure in pregnant women reportedly has been associated with poor cognitive development and neuromotor functioning in childhood, as well as low childhood birth weight. Retail products containing ethanol require federal warning labels directed at notification of potential birth defects and other elements of reproductive consequences.

Aliphatic Solvents