Solvents and VaporsSolvents and Vapors(Volatile Organic Compounds)(Volatile Organic Compounds)

有機溶劑的特性有機溶劑的特性 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)

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

Route of ExposureRoute of Exposure

Primary routeRespiratory

Related to volatility of solventLipid solubilityMAC

Secondary routeSkinIngestion (accident)

Sources of exposureSources 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)

Occupational HealthOccupational HealthTLVsTLVs(Threshold limit values)(Threshold limit values)

There are three categories of ACGIHTLV:

• Time-Weighted Average (TLV-TWA)

•Short-Term Exposure Limit (TLV-STEL)

•Ceiling (TLV-C)

Occupational Standards: TWAOccupational Standards: TWAThe 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

TWATWA

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

Short-Term Exposure Limit Short-Term Exposure Limit (TLV-STEL)(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.

Ceiling (TLV-C)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.

General AcuteToxic EffectsGeneral 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 dosebehavioral toxicity

Dermal and mucous irritation

Solvent-induced chronic Solvent-induced chronic encephalopathy (CSE)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

刺激性或過敏性皮膚炎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。

Biomarkers of solventsBiomarkers 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

MetabolismMetabolism

Metabolic inactivation (detoxification)

tolueneMetabolic activation (bioactivation)

benzene

P450 isozymes exhibit species-, substrate-, and region-selectivity

CYP 2E1 (1)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 acidschlorinated solvents -- chloroform,

trichloroethylene (TCE), carbon tetrachloride, etc. oxidizes benzene (single unsubstituted aromatic

ring)

CYP 2E1 (2)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

MetabolitesMetabolites 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

P450 inducers and inhibitorsP450 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 inhibitors1,2-dichloroethylene vs. CYP2E1

Alkanes and AlkenesAlkanes and Alkenes

Carbon chainsSimple

Straight or branchedGenerally highly volatile and

lipophilicExamples

Pentane, hexane, octanePaint thinners, enamels, varnishes

Alkanes and AlkenesAlkanes and Alkenes

Solubilize or emulsify fats Respiratory Effects

Irritation/swelling of mucous membranesBronchoconstrictionPulmonary edema

CNSAnesthesia and narcosis

Skin Irritation and swelling

Halogenated HydrocarbonsHalogenated HydrocarbonsGeneral 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

Halogenated HydrocarbonsHalogenated Hydrocarbons

Chloroform, dichloromethane, carbon tetrachloride

Heptatoxicity-fatty liver and necrosis

↑numbers of halogens, size , ease of homolytic cleavage→↑toxicity

DichloromethaneDichloromethane(methylene chloride)(methylene chloride)

Solvent for removing paint or degreasing

Removal of caffeine from coffeeToxic effects

CNS depressionMetabolized to CO hypoxia

ChloroformChloroform

Earliest anestheticsAcute effects

Anesthesia, cardiac arrhythmiasChronic effects

Liver damageMetabolism to reactive metabolite

• Phosgene

• Centrilobular necrosis, fatty liver

Kidney damage

Carbon TetrachlorideCarbon Tetrachloride

UsesSolvent, cleaning agent, fire

extinguisherAntihelminthic for humans

ExposureOccupationalFound in groundwater and waste

sites

Carbon TetrachlorideCarbon Tetrachloride

ToxicityHepatotoxic

Forms reactive metabolitesCentrilobular necrosis, fatty liver

2E1

Inhibit microsomal ATPase activity within minutes

Single cell necrosis 5-6 hr

Maximal centrolobular necrosis 24-48 h

CYP2E1 inhibitors can prevent CCl4 toxicity

•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.

Trichloroethylene (TCE)

Kidney tumorsDCVC is bioactivated in proximal tubular cells to reactive thiolS-(1,2-dichlorovinyl)thiol

Liver tumorsExpression of CYP2E1 in the hepatocytesTCA and DCA

Lung cancerChloral hydrate accumulation in Clara cells

TetrachloroethyleneTetrachloroethylene

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

AlcoholsAlcohols Ethyl alcohol

Solvent, intoxicating beverageOccupational exposure minorToxic effects

CNS depression

• Disrupt cell membrane

• Block NMDA receptors Fetal alcohol syndrome Hepatotoxic

• Metabolism to acetaldehyde

• ROS

• Malnutrition

Possible mechanisms of alcoholPossible 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

C O 2 + H 2O

A ce ty l C o A

A ce tic a c id

A ce ta ld ehyd e

E tha n o l

Alcoholdehydrogenase

Aldehyde dehydrogenase

METABOLIC PATHWAYMETABOLIC PATHWAYMETABOLIC PATHWAY

MethanolMethanol

SolventIndustrial exposureToxicity

Permanent blindness• Damages retina and optic nerve

Metabolized to formic acid• Accumulates in tissues

COCO22 + H + H22OO

Formic acid

Formaldehyde

Methanol

Tetrahydrofolate

Alcohol dehydrogenase

Aldehyde dehydrogenase

Methanol intoxicationMethanol intoxication

Neurologic symptoms:headache dizzinessamnesiarestlessnessacute manialethargyconfusioncomaconvulsions

OPHTHALMOLOGIC TOXICITYOPHTHALMOLOGIC 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

TreatmentTreatment • 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

Ethylene GlycolEthylene Glycol

UsesHeat exchangers, antifreeze,

hydraulic fluid, industrial solventsExposure

Vapor or mistGroundwaterAccidental

Ethylene GlycolEthylene Glycol

••AntifreezeAntifreeze

••Sweet, palatableSweet, palatable

••1.5 1.5 teaspoons teaspoons can kill a cat!can kill a cat!

••½½cup can kill a cup can kill a 2020--lb doglb dog

••Very common Very common cause of toxicitycause of toxicity

Clinical Signs Phase IClinical Signs Phase I

••Within 1 hour:Within 1 hour:––Animal Animal appears drunkappears drunk

Clinical Signs Phase IClinical Signs Phase I

•• Within 12 hours:Within 12 hours:–– VomitingVomiting

–– AtaxiaAtaxia

–– PU/PDPU/PD

–– DepressionDepression

–– SeizuresSeizures

Clinical Signs Clinical Signs Phase IIPhase II

•• 2424--96 96 hours after ingestionhours after ingestion–– Calc ium oxalate crystals deposit in Calc ium oxalate crystals deposit in

renal tubules renal tubules ((renal failurerenal failure))

–– blood vessels in the brain (blood vessels in the brain (seizures, seizures, comacoma))

Treatment –the same as methanol

Mechanism of ActionMechanism of Action

Ethylene glycol

Alcohol dehydroenase

Glycoaldehyde

Glycolic acid

Oxalate

Severe acidosis

Renal Failure

Aromatic HydrocarbonsAromatic Hydrocarbons

Benzene, toluene and xyleneMost common aromatic

hydrocarbons found in petroleumHigh volatilityLow water solubilityPriority pollutants

BenzeneBenzene

UsesPetroleum industryStarting material in chemical

synthesisExposure

Primarily workplace Inhalation of benzene vaporsSkin absorption

Benzene ToxicityBenzene Toxicity

Mechanism (Chronic)Conversion of benzene to reactive

metaboliteBenzene oxide Quinones,

semiquinonesInitial reactions LiverFinal reactions Bone marrow

Covalently bind to DNA, RNA and proteinsROS

Benzene MetabolismBenzene Metabolism

o

benzene

benzene oxide

OH

P450

phenol

nonenzymaticrearrangement

SG

glutathioneconjugate

GST/GSH

P450

OH

OH

hydroquinone

O

O

OH

OH

catechol

O

O

1,2-benzoquinone

CHO

CHO

COOH

COOH

t,t-muconaldehyde muconicacid

1,4-benzoquinone

OH

OH

epoxidehydrolase

dihydrodioldehydrogenase

reaction withmacromolecules

reaction withmacromolecules

reaction withmacromoleculessulphate and glucuronide

conjugates

S-phenylmercapturic acid

Biomarkers in Chinese WorkersBiomarkers in Chinese Workers44 controls and 44 workers exposed to high levels of benzene

• Air monitoring (5 air samples over 2 weeks)

• Median benzene exposure (8 hr TWA) - 99 mg/m3 (31 ppm)

• Biomarkers of Exposure (1 blood & 1 urine sample)

• Hb and albumin adducts of benzene oxide & benzoquinone

• urinary metabolites: unmetabolized benzene, phenol,hydroquinone, catechol, muconic acid

• Biomarkers of Effect• hematotoxicity (blood cell counts)

• cytogenetic damage (aneuploidy, translocations)

• Biomarkers of Susceptibility• P4502E1 and NQO1 (quinone reductase) polymorphisms

Toluene and XyleneToluene and XyleneUses

Synthesis of resins, plastics, gasoline additives

Paints, thinners, glues, cleaning agentsExposure

Low levelIndustrial workers, gas station

attendantsToluene more lipophilic than benzene

Toluene and Xylene ToxicityToluene and Xylene ToxicityAcute

Central nervous systemDepression, narcosis

Gastrointestinal disturbancesChronic

Impaired cognition, reaction timesHearing loss

Possible mechanism of CNS effects of toluene

•Change membrane fluidity altering intracellular communication

•Partition into hydrophobic regions of proteins altering membrane –bound enzyme activity and/or receptor activity

•NeurotransmitterEnhance GABAA receptorAttenuate NMDA receptor, nicotinic receptorActivate dopamine systems

Polycyclic Aromatic Polycyclic Aromatic Hydrocarbons (PAHsHydrocarbons (PAHs))

Two or more fused aromatic ringsLarge group of chemicalsPriority pollutantsSources

Incomplete combustion of organic material

Automobiles, manufacturing

Priority PAHs

Benzo(k)fluoranthene Benzo(a)pyrene Dibenz(a,h)anthracene

Indeno(1,2,3-c,d)pyrene Benzo(g,h,i)perylene

Acenaphthene Fluorene

Fluoranthene Benz(a)anthracene

Benzo(b)fluoranthene

Phenanthrene

Anthracene Pyrene Chrysene

Naphthalene Acenaphthylene

EPA Class B2 Carcinogens

PAHsPAHs

TransportReleased into atmosphere

Movement

DepositionSurface waterPlantsSedimentsGround water

PAHsPAHs

ExposureWidely distributed in environmentSurface water

Deposition of airborne PAHs Wastewater discharge, storm water runoff Industrial discharges

Food Grilled/smoked meats Leafy vegetables and grains

Tobacco smoke

PAHsPAHs Exposure

InhalationOralSkin

Stored in kidney and liver Lipophilic

Resistant to degradation in environment Toxicity

Reactive metabolitesPotential carcinogens

HEALTH EFFECTSHEALTH EFFECTS

In addition to skin cancerReports indicating higher incidences

of:Respiratory tract tumorsUpper gastrointestinal tract tumors

Due to occupational exposure of PAHs