Solvents and Vapors (Volatile Organic Compounds)

1. Solvents and Vapors(Volatile Organic Compounds)

2. 有機溶劑的特性 • 溶解性 脂溶性（可溶解脂肪）愈強，去脂效能愈佳，對皮膚和神經系統的傷害也愈大 • 可燃性 可燃性高者作燃料，不可燃者則作滅火劑。 • 揮發性 蒸氣壓愈高，揮發性愈強，空氣中有機溶劑的濃度愈大，愈多經由呼吸道吸入人體。 • 化學結構 一般而言，結構相似者毒性可能相近，例如鹵化有機溶劑（四氯甲烷，三氯乙烯，四氯乙烯等），對肝皆具毒性。也可能差很多， 2,4-diaminotoluene (liver tumor)/2,6-diaminotoluene (not)

3. The main determinants of a solvent’s inherent toxicity • the number of carbon atom • lipophilicity volatility • whether it is saturated or has double or triple bonds between adjacent carbon atoms • its configuration (straight chain, branch chain, or cyclic) • the presence of functional groups • ex. Amides/amines-potent sensitizer • aldehyde-irritating

4. Route of Exposure • Primary route • Respiratory • Related to volatility of solvent • Lipid solubility • MAC • Secondary route • Skin • Ingestion (accident)

5. Sources of exposure • Daily activity-workplace, gas station, smoking, household, etc. • Solvent abuse-produce euphoria, delusions, sedation and visual and auditory hallucination • Environmental contamination major volatile organic solvents (VOCs)

8. Occupational Standards: TWA The time-weighted average is the time-weighted average concentration for a normal 8-hour workday or 40-hour workweek, to which nearly all workers may be repeatedly exposed, day after day, without adverse effect. As shown in the figure, time weighted averages permit excursions above the limit provided that they are compensated by equivalent excursions below the limit during the workweek TWA

9. To illustrate the TWA formula, assume that a substance has an 8-hour time-weighted average PEL of 100 ppm. Assume that an employee is subject to the following exposure: Two hours exposure at 150 ppmTwo hours exposure at 75 ppmFour hours exposure at 50 ppm. Substituting this information in the formula, we have: TWA = (150)(2) + (75)(2) + (50)(4) = 81.25 ppm                              8 Since 81.25 ppm is less than 100 ppm, the 8-hour time-weighted average limit, the exposure is acceptable

10. Short-Term Exposure Limit (TLV-STEL) the maximum concentration to which workers can be exposed continuously for a short period of time (15-minute) without suffering from irritation, chronic or irreversible tissue change, or narcosis of sufficient degree to increase accident proneness, impair self-rescue, or materially reduce work efficiency.

11. Ceiling (TLV-C) • Ceiling (TLV-C) is the concentration that should not be exceeded even instantaneously. • For some substances, for example irritant gases, only the TLV-ceiling may be relevant.

12. General AcuteToxic Effects • CNS depression • High level exposure • 中樞神經麻醉效果，例如乙醚麻醉 一般而言，碳鏈愈長，含雙鍵、鹵素基（氯、溴、氟等）的溶劑中樞效果愈強。臨床上，暴露的人會頭暈、頭痛、噁心、嘔吐、嗜睡，平衡失調，像醉酒一般，除了影響健康外，勞工甚易發生工作意外。工作場所中常存在多種溶劑或混合物，彼此加強作用，危害比單一物質更大。 -Subanesthetic dose behavioral toxicity • Dermal and mucous irritation

13. Solvent-induced chronic encephalopathy (CSE) • Nonspecific symptoms (headache, fatigue, sleep disorders) with or without changes in neuropsychological dysfunction • Type I Symptoms only • Type 2A Sustained personality or mood change • Type 2B Impairment in intellectual function • Type 3 Dementia

14. 刺激性或過敏性皮膚炎 • 有機溶劑具去脂性，能溶解皮膚表面油脂，引起皮膚炎。暴露濃度愈高，時間愈長，或溶劑封閉在手套內無法揮發，造成的傷害愈大。在工廠內有一個動作十分容易傷害皮膚，即是用溶劑來洗手，去除污垢。殊不知長期下來，油脂儘失，往往引起刺激性或過敏性皮膚炎。皮膚炎的臨床表現分急慢性兩種，急性呈紅，腫，慢性呈乾，裂的濕疹樣變化。

15. Biomarkers of solvents • Measurements of blood or urine levels of chemicals following exposure (not highly specific) • Characterization and quantitation of unique metabolites in body fluids • Measurement of covalent binding of reactive metabolites to proteins, lipids, or nucleic acids • Chemically related and specific forms of chromosome damage

16. Metabolism • Metabolic inactivation (detoxification) toluene • Metabolic activation (bioactivation) benzene P450 isozymes exhibit species-, substrate-, and region-selectivity

17. CYP 2E1 (1) • 2E1 active in both hepatic and non-hepatic tissues • substrate preference -- mainly for simple aliphatic compounds (‘solvents’) • oxidizes small straight-chain or branched-chain compounds (no rings) • alcohols (methanol, ethanol), acetone and ketone bodies, short-chain fatty acids • chlorinated solvents -- chloroform, trichloroethylene (TCE), carbon tetrachloride, etc. • oxidizes benzene (single unsubstituted aromatic ring)

18. CYP 2E1 (2) • Bioactivation • aliphatic epoxides and aldehydes are reactive metabolites (liver damage) • benzene epoxide (myelotoxicity) --> bone marrow cell damage --> leukemia • slightly inducible by small aliphatic compounds / also prolongs enzyme activity • ‘EtOH-inducible P450’ (ethanol) --> 2-5 x increase CYP 2E1 levels

19. Metabolites • Generation of biologic reactive intermediates a. Inactivated by glutathione, ascorbic acid and other cellular antioxidants b. covalent bind to cellular macromolecules →inactivation of receptors and specific proteins, damage to cell membranes, or initiation of mutagenic reactions c. Metabolic saturation-detoxication pathway →bioactivation pathway • Generation of reactive oxygen species-free radical, ROS

20. P450 inducers and inhibitors • Inducers-ethanol, acetone, ketones, PAH, certain drugs (phenobarbital, phenytoin, diazepam, rifampicin), smoking • Inhibitors-disulfiram, 3-amino-1,2,4-triazole, several constituents of foods (diallyl sulfide, dihydrocapsaicin, phenylethyl isothio cyanate) • Suicide inhibitors 1,2-dichloroethylene vs. CYP2E1

21. Alkanes and Alkenes • Carbon chains • Simple • Straight or branched • Generally highly volatile and lipophilic • Examples • Pentane, hexane, octane • Paint thinners, enamels, varnishes

22. Alkanes and Alkenes • Solubilize or emulsify fats • Respiratory Effects • Irritation/swelling of mucous membranes • Bronchoconstriction • Pulmonary edema • CNS • Anesthesia and narcosis • Skin • Irritation and swelling

23. Halogenated Hydrocarbons General Structure – H of hydrocarbon replaced by F, Cl, Br, I Names – Halogen named as substituent group F –fluoro Cl - chloro Br-bromo I - iodo – Examples: • dichloromethane = CH2Cl2 • 1,2-dibromoethane = CH2Br-CH2Br

24. Halogenated Hydrocarbons • Chloroform, dichloromethane, carbon tetrachloride • Heptatoxicity-fatty liver and necrosis • ↑numbers of halogens, size , ease of homolytic cleavage→↑toxicity

25. Dichloromethane(methylene chloride) • Solvent for removing paint or degreasing • Removal of caffeine from coffee • Toxic effects • CNS depression • Metabolized to CO hypoxia

26. Chloroform • Earliest anesthetics • Acute effects • Anesthesia, cardiac arrhythmias • Chronic effects • Liver damage • Metabolism to reactive metabolite • Phosgene • Centrilobular necrosis, fatty liver • Kidney damage

27. Carbon Tetrachloride • Uses • Solvent, cleaning agent, fire extinguisher • Antihelminthic for humans • Exposure • Occupational • Found in groundwater and waste sites

28. Carbon Tetrachloride • Toxicity • Hepatotoxic • Forms reactive metabolites • Centrilobular necrosis, fatty liver 2E1

29. Inhibit microsomal ATPase activity within minutes Single cell necrosis 5-6 hr Maximal centrolobular necrosis 24-48 h CYP2E1 inhibitors can prevent CCl4 toxicity

30. Trichloroethylene (TCE) • TCE has multiple effects: • Several forms of cancer. • neurotoxicity, immunotoxicity, developmental toxicity, liver toxicity, kidney toxicity, and endocrine effects. • TCE acts through multiple metabolites and metabolic pathways: • CYP450 metabolites include TCA, DCA. • GST metabolites include DCVC. • . TCE acts through multiple modes of action.

32. Kidney tumors DCVC is bioactivated in proximal tubular cells to reactive thiol S-(1,2-dichlorovinyl)thiol Liver tumors Expression of CYP2E1 in the hepatocytes TCA and DCA Lung cancer Chloral hydrate accumulation in Clara cells

33. Tetrachloroethylene • widely used for dry-cleaning fabrics and metal degreasing operations • liver, kidney, and central nervous system (CNS) from acute and chronic inhalation exposure to tetrachloroethylene • probably carcinogenic to humans

34. Alcohols • Ethyl alcohol • Solvent, intoxicating beverage • Occupational exposure minor • Toxic effects • CNS depression • Disrupt cell membrane • Block NMDA receptors • Fetal alcohol syndrome • Hepatotoxic • Metabolism to acetaldehyde • ROS • Malnutrition

35. Possible mechanisms of alcohol • ↑membrane fluidity→displacement of membrane enzyme and alteration the function of membrane, the reticular activating system is most sensitive • block the NMDA receptor • interfere with ATP-gated ion channel

40. Methanol • Solvent • Industrial exposure • Toxicity • Permanent blindness • Damages retina and optic nerve • Metabolized to formic acid • Accumulates in tissues

41. Methanol Alcohol dehydrogenase Formaldehyde Aldehyde dehydrogenase Formic acid Tetrahydrofolate CO2 + H2O

42. Methanol intoxication • Neurologic symptoms: • headache • dizziness • amnesia • restlessness • acute mania • lethargy • confusion • coma • convulsions

43. OPHTHALMOLOGIC TOXICITY • Target-retina-optic disk and optic nerve • Occur when serum pH drops below 7.2 • Low pH  intracellular concentration of formate • Improvement of vision with correction of acidosis, because formate moves out of the cell • Formate is an inhibitor of cytochrome oxidase, which could inhibit ATP formation in the optic nerve

44. Treatment • Ethanol therapy • Hemodialysis effectively removes methanol and its toxic metabolites • 4-methylpyrazole (4-MP) “Fomepizole”: a more potent inhibitor of alcohol dehyrogenase • Folate therapy • Sodium bicarbonate

45. Ethylene Glycol • Uses • Heat exchangers, antifreeze, hydraulic fluid, industrial solvents • Exposure • Vapor or mist • Groundwater • Accidental

49. Treatment –the same as methanol