1 Neurotoxic Effects from Exposure to Organic Solvents

2 Organic Solvent Solvent: any substance that dissolves another substance resulting in a solution. Solvents may be aqueous (water-based) or organic (hydrocarbon-based). An organic solvent is lipophilic and a volatile liquid at room temperature. Organic solvents are most commonly used for cleaning, degreasing, thinning.

3 Methyl Ethyl Ketone

4 Perchloroethylene

5 Trichloroethylene (TCE)

6 Toluene

7 Peripheral Neuropathy: This is not a common consequence of severe solvent exposure, exceptions being exposure to: n-hexane carbon disulphide methyl-n-butyl ketone styrene trichloroethylene n-Hexane is widely used in quick drying rubber cements, glues, inks and varnishes and may only be revealed when a material safety data sheet (MSDS) is obtained from the manufacturer.

8 Central Nervous System Effects Acute Central Nervous System Effects Almost all volatile lipid-soluble organic chemicals cause general non-specific depression of the CNS (or general anesthesia). Beginning with ethyl ether a number of industrial solvents were used historically as surgical anesthetics.

9 Central Nervous System Effects (continued) Acute Central Nervous System Effects Clinical Findings: Symptoms and Signs headache, nausea & vomiting, dizziness, light-headedness, vertigo, disequilibrium, slurred speech, euphoria, fatigue, sleepiness, weakness, irritability, nervousness, depression, disorientation, and confusion loss of consciousness and death (from respiratory depression) secondarily, an increase in risk of accident

10 Chronic Neurobehavioral Effects Of Exposure To Organic Solvents Acute neurobehaviorial effects of solvents have been long recognized and accepted. Controversy concerns potential chronic effects including the reversibility of any such effects. In the 1970s and early 1980s, a series of case control studies conducted almost entirely in Scandinavian countries mostly among painters reported significant associations between chronic, irreversible neurobehavioral effects including dementia and putative workplace exposure to organic solvents. Some reported a clear dose response suggesting that current exposure limits were inadequate to protect against these effects.

11 Chronic Toxic Encephalopathy The described disease entity was labeled as “painter’s syndrome”, or “psycho-organic syndrome” or more broadly (solvent -related) “chronic toxic encephalopathy.” Characteristic described features were: long-term low to moderate level solvent exposure, neuropsychiatric symptoms (fatigue, memory impairment, concentration difficulties) defects in perceptual and psychomotor functions tests frank dementia in severe cases Other features sometimes described included: brain atrophy changes in regional cerebral blood flow changes in cerebrospinal fluid proteins

12 Chronic Toxic Encephalopathy Many of these studies were criticized for purported lack of adequate control of confounding and inaccurate assessment of exposure. Similar studies conducted in other countries, especially the United States, produced much more mixed results. Because of these concerns, several important consensus conferences were held in the early to mid-1980s. While many of the controversial issues were not resolved, there was agreement on common nomenclature.

International Solvent Workshop Classification Type 1 (the least severe) Characterized by fatigue, memory impairment, irritability, difficulty in concentrating, and mild mood disturbance. This corresponds to the WHO classification of organic affective syndrome. It is reversible on removal from exposure.

14 Clinical Manifestations and Causes of CNS Conditions II. Chronic syndromes Carbon disulfide, lead, organic solvents ReversibleWeeks to months No objective signs Mood changes (irritability, depression), sleep disorders; difficulty concentrations; memory complaints; symptoms more noticeable to relative than to patient 1. Symptoms only Major Neurotoxic Substances Prognosis following Cessation of Exposure LatencySignsSymptomsCondition

International Solvent Workshop Classification Type 2 Symptoms of neurotoxicity and abnormalities of performance on neuropsychological testing. Type 2 disorder has been subdivided into: Type 2A: sustained personality or mood change Type 2B: impairment in intellectual function. This level corresponds to the WHO classification of mild chronic toxic encephalopathy.

16 Clinical Manifestations and Causes of CNS Conditions II. Chronic syndromes (continued) Incomplete reversibility possible but uncommon Weeks to months Mood or personality inventories of potential value Similar to “symptoms only” but with greater frequency and severity 2a. Organic personality or mood disorder Prognosis following Cessation of Exposure LatencySignsSymptomsCondition Mild chronic toxic encephalopathy

17 Clinical Manifestations and Causes of CNS Conditions II. Chronic syndromes (continued) Potentially reversible, partial or complete Weeks to months Reduced motor speed, reduced vigilance and reaction time, reduced performance on memory (short-term) testing and other tests of cognitive function (ie, visuo-spatial ability) Symptoms as in 2a (previous slide) may be present 2b. Neurobehavioral impairment Prognosis following Cessation of Exposure LatencySignsSymptomsCondition Mild chronic toxic encephalopathy

International Solvent Workshop Classification Type 3 (most severe) Global deterioration in intellectual and memory functions (dementia). This corresponds to the WHO classification of severe chronic toxic encephalopathy and is usually irreversible.

19 Clinical Manifestations and Causes of CNS Conditions III. Severe chronic toxic encephalopathy (dementia) Poorly reversibleTesting compatible with severe neurological damage and severe neuropsychologcal impairment as seen in dementia Significant loss of ability to perform activities of daily Severe chronic toxic encephalopathy (dementia) Prognosis following Cessation of Exposure SignsSymptomsCondition

20 Chronic Toxic Encephalopathy At a scientific meeting in Montreal in 1990, the following summary statement was presented: A critical review gives convincing evidence that long- term occupational exposure to solvents may lead to chronic disorders of the nervous system in man. Firstly, studies independent of each other indicating a chronic disorder by far outnumber the few studies which do not indicate an effect. Secondly, the non-confirming studies do not differ in scientific quality from the other studies compensating for quantity. Thirdly, quantitative and qualitative differences in solvent exposure may explain differences in study results.

21 Chronic Toxic Encephalopathy More recently (1994), a review has been carried out by Edward Baker at the CDC, Atlanta, of research performed since This review found a consistency between the studies and with studies published before 1985 and demonstrated short-term memory and psychomotor functional damage as well as a dose-response relationship.

22 Chronic Toxic Encephalopathy The neurobehavioral effects noted in this review were: solvent-exposed workers demonstrate decrements in short-term memory and psychomotor functions in most studies there was a dose-response relationship the neurobehavioral defects are similar to those seen in heavily exposed solvent workers and those with pronounced neurobehavioral dysfunction due to solvent abuse.

23 Critical Issues in Assessing Studies Of Neurotoxic Effects of Organic Solvents 1. To which specific agent or combination of agents are the study subjects potentially exposed? 2. What are the levels of exposure to these agents? Is reliable quantitative data available? How and with what confidence were exposure levels estimated? Are the levels of exposures sufficient to reasonably expect that they could produce the outcomes being evaluated?

24 Critical Issues In Assessing Studies Of Neurotoxic Effects Of Organic Solvents 3. What is the overall study design? If the study is cross-sectional or case control (as opposed to prospective within inception cohort): are issues of selection bias addressed adequately? Also, are the solvent exposed and solvent unexposed comparable with respect to confounding exposures prior to and during the period of employment? 4. Which domains of neurobehavioral response are reported as been affected by exposure? Is their consistency in the pattern of the affected domains across various studies?

25 Chronic Solvent Toxic Encephalopathy Diagnosis of Chronic Solvent Toxic Encephalopathy Like all occupationally-related conditions the following procedures are necessary to make an occupationally- related diagnosis of chronic solvent toxic encephalopathy: 1. A careful occupational history and possibly including a workplace visit and measurement of the environmental hazard.

26 Chronic Solvent Toxic Encephalopathy 2. A careful clinical history noting any temporal relationship between exposure and symptoms and utilizing the 1985 International Solvent Workshop Classification.

27 Type l and 2 disorders are the most likely to be reported among solvent-exposed workers. Type 3 disorders have largely been restricted to individuals who have abused solvent-containing products (by deliberately inhaling organic solvent vapors for their euphoric properties). For example, persons who abusively inhaled toluene almost daily for 1-7 years showed evidence of severe, multifocal CNS damage with cortical, cerebellar, and brain stem atrophy, electrophysiologic abnormalities, and neuropsychologic deficits (Lazar et al. 1983).

28 Chronic Solvent Toxic Encephalopathy 3. Measurement of central nervous system impairment with objective changes in neuro- psychological tests carried out by a clinical psychologist with experience in testing solvent- affected workers.

29 Chronic Solvent Toxic Encephalopathy 4.Other investigations such as EEG, evoked potentials, electroneuro-myography, computed CT, MRI etc. 5.The exclusion of other causes for chronic neurotoxic effects. The diagnosis should thus be made on an assessment of a range of investigations and a final consensus rather than on any one particular result.