Organic Solvent Neurotoxicity: Background, Pathophysiology, Epidemiology

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Sections Organic Solvent Neurotoxicity
Overview
Presentation
- History
- Physical
- Causes
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DDx
Workup
Treatment
Medication
Follow-up
Tables
References

Overview

Background

Organic solvents are a chemical class of compounds that are used routinely in commercial industries. They share a common structure (at least 1 carbon atom and 1 hydrogen atom), low molecular weight, lipophilicity, and volatility, and they exist in liquid form at room temperature. They may be grouped further into aliphatic-chain compounds, such as n -hexane, and as aromatic compounds with a 6-carbon ring, such as benzene or xylene. Aliphatics and aromatics may contain a substituted halogen element and may be referred to as halogenated hydrocarbons, such as perchloroethylene (PCE or PER), trichloroethylene (TCE), and carbon tetrachloride. Alcohols, ketones, glycols, esters, ethers, aldehydes, and pyridines are substitutions for a hydrogen group. Organic solvents are useful because they can dissolve oils, fats, resins, rubber, and plastics.

Organic solvents arose in the latter half of the 19th century from the coal-tar industry. Their application grew to be wide and diverse in both developed and developing countries. The introduction of chlorinated solvents in the 1920s led to reports of toxicity. Although solvents number in the thousands, only a few have been tested for neurotoxicity.

Workers in industries that use these agents may have occupational exposure, whereas other individuals may have environmental exposures if they live near industrial installations and/or have contact with contaminated water, soil, air, or food. Drinking water, shower water, ambient air, indoor air, and food, among other sources, are common routes of exposure to environmental toxins.^[1]Inhalation, ingestion, and dermal absorption are also important mechanisms of toxic exposure.^{[2, 3, 4]}Exposures often involve mixtures of solvents. Some of these incidents may occur deliberately when an individual recreationally inhales paints, glues, and other products; these exposures are described in more detail in the Medscape Reference article Inhalants.

The Occupational Safety and Health Administration (OSHA) regulates worker exposure. The National Institute for Occupational Safety and Health (NIOSH) and the American Congress of Governmental Industrial Hygienists (ACGIH) also publish standards for use in occupational settings in the United States.

Pathophysiology

Short-term, high-level exposures such as those frequently reported in case reports can result in acute reversible and irreversible health effects that involve the CNS and PNS. In population studies, intermediate- and long-term, low-level exposures have led to reversible and nonreversible subclinical and clinical abnormalities in the CNS and PNS. In some cases, these exposures were estimated to be below acceptable levels, as designated in regulations for workers. Neurophysiologic, neuropsychological, and neuroimaging diagnostic tools have been used to evaluate individuals and groups exposed to organic solvents.

Frequency

United States

In 1987, NIOSH reported that 9.8 million workers were exposed to organic solvents in occupational settings. However, most occupational exposures involved solvent mixtures. Workers who use these agents include printers, paint manufacturers, painters, microelectronics workers, degreasers, dry cleaners, carpet layers, coating workers, gluers, dye workers, carpenters, anesthesia personnel, petrol filling workers, laboratory workers, inkers, and textile workers; others are those who work with polymers, pharmaceuticals, synthetic fabrics, agriculture products, refining, or in airplane refitting. Table 1 lists common sources of organic solvent exposures.

Table 1. Organic Solvents and Their Common Industrial Uses (Open Table in a new window)

Compound	Industrial Uses
Acetone	Cleaning solvent
Acrylamide	Mining and tunneling, adhesives, waste treatment, ore processing
Benzene	Fuel, detergents, paint removers, manufacture of other solvents
Carbon disulfide	Viscose rayon, explosives, paints, preservatives, textiles, rubber cement, varnishes, electroplating
Ethylene oxide (ETO)	Instrument sterilization
N- hexane	Glues and vegetable extraction, components of naphtha, lacquers, metal cleaning compounds
Hydrogen sulfide	Sulfur chemical manufacturing, by-product of petroleum processing, decay of organic matter
Methane	Industrial settings
Methyl mercaptan	Odorant in natural gas and fuels
Methyl-N- butyl ketone	Many industrial uses
Methylene chloride (dichloromethane)	Solvent, refrigerant, propellant
Organochlorine	Insecticides
Organophosphates	Insecticides
PCE	Dry cleaning, degreaser, textile industry
Styrene	Fiberglass component, ship building
Toluene	Paint, fuel oil, cleaning agents, lacquers, paints and paint thinners
1,1,1-Trichloroethane (methyl chloroform)	Degreaser and propellant
TCE	Cleaning agent, paint component, decaffeination, rubber solvents, varnish
Vinyl chloride	Intermediate for polyvinylchloride resins for plastics, floor coverings, upholstery, appliances, packaging
Xylene	Paint, lacquers, varnishes, inks, dyes, adhesives, cements, fixative for pathologic specimens

Environmental exposures to organic solvents occur. Solvents are also present in home products. According to NIOSH, 49 million tons of organic solvents were produced in the United States in 1984. Contamination affecting community water supplies, food additives, or household chemicals is an important source of exposure. Well-water sampling, both in the United States and abroad, has revealed quantities of chlorinated hydrocarbons and other solvents. Health effects secondary to these exposures have been described.

Estimating rates of occupational exposure is difficult because of a variety of factors. Worker exposures vary even within the same job, exposures vary during a workday, many routes of absorption are possible, personal protective equipment (PPE) is used inconsistently, and solvents are commonly used in various mixtures. For environmental exposures, similar challenges exist. Industrial hygienists and risk-assessment scientists work to overcome these challenges.

Age

Occupational exposures affect persons of working age. Environmental exposures affect persons of all ages.

Clinical Presentation

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Wegman DH, Levy BS, Halperin WE. Occupational Health. Levy BS, Wegman DH, eds. Recognizing occupational disease. 3rd ed. Boston, MA: Little Brown & Company; 1994.
Williams JM, Howe NR. Benzyl alcohol attenuates the pain of lidocaine injections and prolongs anesthesia. J Dermatol Surg Oncol. 1994 Nov. 20(11):730-3. [Medline].

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Table 1. Organic Solvents and Their Common Industrial Uses

Compound	Industrial Uses
Acetone	Cleaning solvent
Acrylamide	Mining and tunneling, adhesives, waste treatment, ore processing
Benzene	Fuel, detergents, paint removers, manufacture of other solvents
Carbon disulfide	Viscose rayon, explosives, paints, preservatives, textiles, rubber cement, varnishes, electroplating
Ethylene oxide (ETO)	Instrument sterilization
N- hexane	Glues and vegetable extraction, components of naphtha, lacquers, metal cleaning compounds
Hydrogen sulfide	Sulfur chemical manufacturing, by-product of petroleum processing, decay of organic matter
Methane	Industrial settings
Methyl mercaptan	Odorant in natural gas and fuels
Methyl-N- butyl ketone	Many industrial uses
Methylene chloride (dichloromethane)	Solvent, refrigerant, propellant
Organochlorine	Insecticides
Organophosphates	Insecticides
PCE	Dry cleaning, degreaser, textile industry
Styrene	Fiberglass component, ship building
Toluene	Paint, fuel oil, cleaning agents, lacquers, paints and paint thinners
1,1,1-Trichloroethane (methyl chloroform)	Degreaser and propellant
TCE	Cleaning agent, paint component, decaffeination, rubber solvents, varnish
Vinyl chloride	Intermediate for polyvinylchloride resins for plastics, floor coverings, upholstery, appliances, packaging
Xylene	Paint, lacquers, varnishes, inks, dyes, adhesives, cements, fixative for pathologic specimens

Table 2. Exposure levels Believed Safe for Workers

Compound	Urine	Blood	Expired Air
Acetone	Acetone, formic acid 100 mg/L	Acetone	Acetone
Benzene	Total phenol 50 mg/g at the end of the shift, trans-trans- muconic acid	Benzene	Benzene before shift, 0.08 ppm; end exhaled, 0.12 ppm
Carbon disulfide	2-TTCA 5 mg/g^*	Carbon disulfide	Carbon disulfide
ETO	None	None	None
N- hexane	2,5-hexanediol 5 mg/g at the end of the shift, 2-hexanol, total metabolites	N- hexane	N- hexane
Hydrogen sulfide	None	None	None
Methane	None	None	None
Methyl mercaptan	None	None	None
Methanol	Formic acid 80 mg/g at the start of the work week, methanol 15 mg/g at the end of the shift	None	Methanol
Methyl-N- butyl ketone	None	2,5-hexane dione	None
Methylene chloride	None	MeCl₂	MeCl₂
Organochlorine	None	None	None
Organophosphates	None	None	None
PCE	PCE, trichloroacetic acid	PCE 1 mg/L	PCE 10 ppm before the last shift of the week
Styrene	End of the shift: mandelic acid (MA) 800 mg, phenylglyoxylic acid (PGA) 240 mg/g) Before shift: MA 300 mg/g or PGA 100 mg/g	Styrene 0.02 mg/L at the start of the shift, 0.55 mg/L at the end of the shift	None
Toluene	Hippuric acid	Toluene	Toluene
1,1,1-Trichlorethane (methyl chloroform)	TCA 10 mg/L at the end of the work week; total trichloroethanol at the end of the shift and at the end of the work week, 30 mg/L	Total trichloroethanol 1 mg/L	Methyl chloroform 40 ppm before the last shift of the work week
TCE	TCE, TCA 100 mg/g at the end of the work week or TCA plus trichloroethanol 300 mg/g	TCE at the end of the work week 4 mg/L	TCE
Vinyl chloride	None	None	None
Xylene	Methylhippuric acid 1.5 g/g at the end of the shift	Xylene	Xylene
^* TTCA - 2-thiothiazolidine 4-carboxylic acid.

Table 3. Recommended Exposure Limits, Organic Solvents

Compound	ppm, mg/m,³
Compound	OSHA PEL as TWAs	NIOSH REL as TWAs, IDLH	ACGIH TLV, STEL
Acetone	1000 (2400)	250 (590), 2500	750 (1780) ceiling, 1000 (2380)
Acrylamide	0.3	(0.03), 60 level for carcinogenicity	None
Benzene	10, 25 ceiling, 50 for 10 min	0.1, STEL 1, 500	10 (32)
Carbon disulfide	20, 30, 100 for 30 min	1 (3), 10 STEL (30), 500	10 (31)
ETO		< 0.1, < 0.18, 5 ceiling, 800	1 (1.8)
N- hexane	500 (1800)	50 (180), 1100	50 (176)
Hydrogen sulfide	20 ceiling, 50 for 10 min once only	10 ceiling, (15) for 10 min, 100	None
Methyl mercaptan	10 ceiling (20)	0.5 ceiling, (1) for 15 min, 150	None
Methanol	200 (260)	200 (260), 250 STEL (325), 6000	262 (200), 328 (250)
Methyl-n- butyl ketone	100 (410)	None	5 (20)
Methylene chloride	25, 15 STEL for 15 min	2300 level for carcinogenicity	50 (174) ceiling
Perchloroethylene	100, 200 ceiling, 300 for 5 min in 3 h	150 level for carcinogenicity	25 (170), 100 (685)
Styrene	100, 200 ceiling, 600 for 5 min in 3 h	50 (215), 100 ST (425), 700	50 (213), 100 (428)
Toluene	200, 300, 500 for 10 min	100 (375), 150 STEL (560), 500	50 (188)
1,1,1-Trichlorethane (methyl chloroform)	350 (1900)	Ceiling 350 (1900) for 15 min, 700	350 (1910), 450 (2460)
Trichloroethylene	100, 200 ceiling, 300 for 5 min in 2 h	1000 level for carcinogenicity	50 (269), 100 (1070)
Vinyl chloride	1, 5 for 15 min	Not determined	None
Xylene	100 (435)	100 (435), 150 STEL (655)	100 (434),150 (651)
Abbreviations—ACGIH = American Congress of Governmental Industrial Hygienists, IDLH = Immediately dangerous to life or health; NIOSH = National Institute for Occupational Safety and Health, OSHA = Occupational Safety and Health Administration, PEL = permissible exposure limit, REL = recommended exposure limit; STEL = short-term exposure limit; TWA = time-weighted average.

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Author

Jonathan S Rutchik, MD, MPH, FACOEM Associate Clinical Professor, Division of Occupational Medicine, Department of Medicine, University of California, San Francisco, School of Medicine; Neurology, Environmental and Occupational Medicine Associates (www.neoma.com)

Jonathan S Rutchik, MD, MPH, FACOEM is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, American College of Occupational and Environmental Medicine, International Parkinson and Movement Disorder Society, Society of Toxicology, Western Occupational and Environmental Medical Association

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Glenn Lopate, MD Associate Professor, Department of Neurology, Division of Neuromuscular Diseases, Washington University in St Louis School of Medicine; Consulting Staff, Department of Neurology, Barnes-Jewish Hospital

Glenn Lopate, MD is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, Phi Beta Kappa

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Alnylam Pharmaceuticals<br/>Received income in an amount equal to or greater than $250 from: Alnylam Pharmaceuticals; GLG.

Chief Editor

Tarakad S Ramachandran, MBBS, MBA, MPH, FAAN, FACP, FAHA, FRCP, FRCPC, FRS, LRCP, MRCP, MRCS Professor Emeritus of Neurology and Psychiatry, Clinical Professor of Medicine, Clinical Professor of Family Medicine, Clinical Professor of Neurosurgery, State University of New York Upstate Medical University; Neuroscience Director, Department of Neurology, Crouse Irving Memorial Hospital

Tarakad S Ramachandran, MBBS, MBA, MPH, FAAN, FACP, FAHA, FRCP, FRCPC, FRS, LRCP, MRCP, MRCS is a member of the following medical societies: American College of International Physicians, American Heart Association, American Stroke Association, American Academy of Neurology, American Academy of Pain Medicine, American College of Forensic Examiners Institute, National Association of Managed Care Physicians, American College of Physicians, Royal College of Physicians, Royal College of Physicians and Surgeons of Canada, Royal College of Surgeons of England, Royal Society of Medicine

Disclosure: Nothing to disclose.

Additional Contributors

Roberta J Seidman, MD Associate Professor of Clinical Pathology, Stony Brook University; Director of Neuropathology, Department of Pathology, Stony Brook University Medical Center

Roberta J Seidman, MD is a member of the following medical societies: American Academy of Neurology, Suffolk County Society of Pathologists, New York Association of Neuropathologists (The Neuroplex), American Association of Neuropathologists

Disclosure: Nothing to disclose.

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