solvents and vapors (volatile organic compounds)
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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