Week #4Toxic effects of solvents and vapors

Assist. Prof. Dr. Bushra Hassan MaroufUniversity of Sulaimani - College of Pharmacy

Week #4

Toxic effects of solvents and vapors

May 08, 2021 Toxicology 4th year 1

Solvents

l Solvents: are liquid organic chemicals with variable lipophilicity and volatility, small molecular size, and lack of charge


Classes of solvents include:

l Aliphatic hydrocarbons, many of which are chlorinated (i.e., halocarbons);

l Aromatic hydrocarbons; l Alcohols; l Ethers; l Esters/acetates; l Amides/amines; l Aldehydes; l Ketones;


Class generalizations of solvent regarding toxicity

l The more lipophilic a hydrocarbon, the more potent a central nervous system (CNS) depressant it is;

l Amides/amines tend to be potent sensitizers; l Aldehydes are particularly irritating;l Hydrocarbons that are extensively metabolized tend to be

more cytotoxic/mutagenic; and many unsaturated, short chain halocarbons are animal carcinogens.


Solvent-Induced Chronic Encephalopathy?

l Is a condition induced by chronic, low-level exposure to organic solvents, typically in the workplace, that lead to a wide variety of persisting sensorimotor polyneuropathies and neurobehavioral deficits even after solvent exposure has been removed. This syndrome can also referred to as

l painter's syndrome,l organic solvent syndrome,l psychoorganic syndrome


Chronic solvent encephalopathy (CSE)

l CSE is characterized by nonspecific symptoms (e.g., headache, fatigue, sleep disorders) with or without changes in neuropsychological function


Routes of Solvent Exposure

l Inhalationl Absorption

-skin-mucous membranes

l Ingestionl Injection

Jane Norling GraphicMay 08, 2021 Toxicology 4th year 7

Solvent Abuse !

l Inhalants are volatile substances that can be inhaled to induce a psychoactive or mind-altering effect with vapor concentrations to produce effects that resemble alcohol intoxication and may lead to unconsciousness.

l Solvent abuse is a unique exposure situation, in that participants repeatedly subject themselves to vapor concentrations.

l Solvents can be breathed in through the nose or the mouth by “sniffing” or “snorting” vapors from containers; spraying aerosols directly into the nose or mouth; “bagging” by inhaling vapors from a plastic or paper bag;


Solvent Abuse !

l Many solvents are inhaled intentionally, and people achieve a state of intoxication with euphoria, delusions, and sedation as well as visual and auditory hallucinations.

l Solvents can be addicting and often are abused in combination with other drugs.

l Solvents are present in relatively inexpensive household and commercial products that are readily available to children and adolescents.

l Death may be a consequence of cardiac arrhythmias, asphyxiation, and/or cachexia


Sniffing


Factors influencing solvents toxicity

l Endogenous Factorsü Childrenü Elderlyü Geneticsl Exogenous Factorsü P450 Inducers and Inhibitorsü Physical Activityü Diet


Endogenous Factors:1. Children (The toxic response is differ?)

l Systemic absorption of inhaled Volatile Organic Compounds (VOCs) may be greater in infants and children than it is in adults owing to the relatively high cardiac output and respiratory rates in children despite their lower alveolar surface area.


1. Children; (The toxic response is differ?)

l Body fat content is high from ½ year to 3 years of age, Lipophilic solvents accumulate in adipose tissue, and so more body fat results in greater body burdens and slower clearance of chemicals.

l Changes in xenobiotic metabolism during maturation may affect susceptibility to solvent toxicity and carcinogenicity.


Children;(The toxic response is differ?)


l Extracellular water (expressed as a percentage of body weight) is highest in newborns and gradually diminishes through childhood.

l The larger volume of distribution for water-soluble solvents results in their slower clearance and longer duration of action.

2. Elderly

Age Influences

Distribution of xenobiotic

Metabolism of xenobiotic

Elimination of xenobiotic


2.Elderly

l With aging, body fat usually increases substantially at the expense of lean mass and body water. Relatively lipid-soluble solvents accumulate in adipose tissue and are released slowly.

l Cardiac output, renal and hepatic blood flows are diminished in the elderly.

l The elderly, like infants and children, may be more sensitive to the toxicity of solvents than young adults are.

l Greater organ system toxicity could be due to increased inflammatory damage or to age-related dysregulation of cytokines.


2.Elderly

l Other major sources of variability and complexity in geriatric populations include inadequate nutrition, the prevalence of disease states, and the concurrent use of multiple medications (polypharmacy).


3.Genetics

l Genetic polymorphisms for biotransformation occur at different frequencies in different ethnic groups. Polymorphisms for phase I and phase II xenobiotic metabolizing enzymes may affect the outcomes of solvent exposures in different racial groups.

l E.g : 50% of Asians have inactive Acetaldehyde dehydrogenase (ALDH)

l Alcohol flushing response or:l “Asian flush”l “Asian glow”


Exogenous Factors:1: P450 Inducers and Inhibitors:l Inhibitors and/or inducers of Cytochrome P450s, Phase II

enzymes, and efflux transporters are being identified. l Inhibitors generally would be anticipated to enhance the

toxicity of solvents that are metabolically inactivated and to provide protection against solvents that undergo metabolic activation. e,g TCE (toxicity due to metabolites)

l Ginko biloba, frequently used for memory impairment, were potent inhibitors of human recombinant CYP1B1, CYP1A1, and CYP1A


Exogenous Factors: 2: Physical Activity

l Exercise increases alveolar ventilation and cardiac output/pulmonary blood flow (two of the major determinants of VOC uptake)

l Heavy exercise can increase the pulmonary uptake of relatively polar solvents as much as fivefold in human subjects.

l Light exercise doubles uptake of relatively lipid-soluble solvents.l Blood flow to the liver and kidneys diminishes with exercise,

which may diminish the biotransformation of metabolized solvents and urinary elimination.


Exogenous Factors; Diet:

l Bulk food in the stomach and intestines can inhibit systemic absorption of ingested chemicals.

l Food intake results in increased splanchnic blood flow, which favors GI absorption, hepatic blood flow, and biotransformation.

l Foods may contain certain natural constituents, pesticides, and other chemicals that may enhance or reduce solvent metabolism

l In addition, fasting for 1 to 3 days results in decreased detoxification of electrophilic metabolites and the formation of cytotoxic, mutagenic metabolites.


Chlorinated Hydrocarbons:

Trichloroethylene (TCE)Tetrachloroethylene

(Perchloroethylene) or “Perc”


Trichloroethylene (TCE)

l Industrial degreasing agentl Solvent used in dry cleaning solutions, paint removers,

cosmetics, adhesives, household cleaners, and spot removers.

l TCE was used as an anestheticl Cancer remains the dominant issue for TCE.


Metabolism and mechanism of TCE toxicity

l Toxicities associated with TCE are mediated predominantly by metabolites rather than by the parent compound.

l Even the central nervous system-depressant effects of TCE are due in part to the sedative properties of the metabolite trichloroethanol (TCOH).



l After oral or inhalational absorption, most of the TCE undergoes oxidation via cytochrome P450s, with a small proportion being conjugated with glutathione (GSH)(scheme)



Two distinct metabolic pathways exist for TCE:


TCE

Oxidative pathway Glutathione (GSH) pathway

Oxidative pathway:

l Their metabolites rapidly undergo oxidation and/or reduction to yield trichloroacetate (TCA) and TCOH, the major end products of the oxidative pathway.

l TCOH is either oxidized to TCA or glucuronidated. TCOH glucuronide is excreted via the urine and bile.

l TCA accumulates in the body due to strong plasma protein binding and slow excretion.


Glutathione pathway:

l Product of GST pathway; Dichlorovinyl glutathione (DCVG) is then effluxed from the hepatocyte into plasma and bile for translocation to the kidney and small intestine respectively.

l DCVG is a minor product it may be detoxified or bioactivated to reactive thiol in renal proximal tubular cells, this reactive metabolite of GSH pathway have genotoxic effect on proximal tubular cells.




3 initial metabolites

Carcinogenicity of TCE

l Both metabolic pathways are implicated in the carcinogenicity of TCE: reactive metabolite(s) of the GSH pathway in kidney tumors and oxidative metabolites in liver and lung


Tetrachloroethylene (Perchloroethylene);PERC

l Use: dry cleaning, metal degreasing, fabric finisher, degreaser, rug and upholstery cleaner, paint and stain remover, solvent, and chemical intermediate.


Dry Cleaners

l Perchloroethylene detected in co-located apartments

l Residents may show poor visual function or other problems


Tetrachloroethylene (Perchloroethylene);PERC

l The highest exposures usually occur in occupational settings through inhalation

l Toxicity: central nervous system depression. l Chronic exposure may adversely affect the neurological

system, liver, and kidneys. l Tetrachloroethylene is reasonably anticipated to be a human

carcinogen


Metabolism and toxicity of PERC

l The systemic disposition and metabolism of PERC and TCE are quite similar. Both chemicals are well absorbed from the lungs and GI tract, distributed to tissues according to their lipid content, partially exhaled unchanged, and metabolized by P450s.

l PERC is oxidized by hepatic P450s to a much lesser degree than is TCE, though the two have a common major metabolite: trichloroacetic acid.

l GSH conjugation is a minor metabolic pathway quantitatively for TCE and PERC.


Metabolism and toxicity of PERC

l Reactive metabolite can covalently bind to proteins and other macromolecules, or react with water to form DCA (dichloroacetate).

l Metabolic products are the primary contributors to PERC-induced nephrotoxicity.


Alcohols:

l Ethanol (Ethyl alcohol, alcohol)l Ethyl alcohol is widely available as beverage, it is an

important constituent of cosmetics, after shave, hair tonic , mouthwash, dishwashing detergents, it is also used as a solvent in industry, in many household products and pharmaceuticals.

l Driving under the influence of alcohol is the major cause of fatal auto accidents.

l The blood level in an average adult decreases by ≈16 mg% (16mg /100ml of blood) per hour. Thus, a person with a blood alcohol level (BAC) of 120 mg% would require ≈8 hours to reach negligible levels.


Fetal Alcohol Syndrome (FAS)

l Fetal alcohol syndrome is growth, mental, and physical problems that may occur in a baby when a mother drinks alcohol during pregnancy. The diagnostic criteria for FAS include:

(1) Heavy maternal alcohol consumption during gestation, (2) Pre- and postnatal growth retardation, (3) Craniofacial malformations, including microcephaly, (4) Mental retardation.




Fetal Alcohol Syndrome (FAS) brain




Alcohol and cancers

l Chronic ethanol consumption may promote carcinogenesis. Ethanol and smoking act synergistically to cause oral, pharyngeal, and laryngeal cancers.

l It generally is believed that alcohol induces liver cancer by causing cirrhosis or other liver damage and/or by enhancing the bioactivation of carcinogens


Possible mechanisms of ethanol carcinogenicity

Congeners, additives, and contaminants in alcoholic beverages influence carcinogenicity.CYP2E1 induction by ethanol increases metabolic activation of procarcinogens.Ethanol acts as a solvent for carcinogens, enhancing their absorption into tissues in the upper GI tract.Ethanol affects the actions of certain hormones in hormone-sensitive tissues.Immune function is suppressed by alcohol.Absorption and bioavailability of nutrients are reduced by alcohol.


Methanol (methyl alcohol, wood alcohol)

l Methanol is found in many products, including windshield washer fluid.

l There are 2 stages of poisoning l Early stage of poisoning?l Late stage of poisoning?

CH3—OH


Methanol metabolism and toxicity l CH3OH is metabolized in the liver by alcohol dehydrogenase

(ADH) to formaldehyde (HCOH), which in turn is very rapidly converted via aldehyde dehydrogenase (ALDH) (formaldehyde dehydrogenase) to formate.

l Although methanol is metabolized in the liver, intraretinalconversion of methanol to formaldehyde and formate is critical. Metabolism of formate to CO2 then occurs through tetrahydrofolate (THF)-dependent pathway. Susceptibility to methanol toxicity is dependent on the relative rate of formateclearance.

l Formate acts as a direct ocular toxin, l and the acidotic state potentiates formate toxicity because the

inhibition of cytochrome oxidase increases as pH decrease


Methanol metabolism and toxicity


Methanol metabolism and toxicity

l Acute methanol poisoning in humans is characterized by an asymptomatic period of 12 to 24 h followed by formic acidemia, ocular toxicity, coma, and in extreme cases death.

l Visual disturbances develop between 18 and 48 h after ingestion and range from mild photophobia and blurred vision to markedly reduced visual acuity and complete blindness.

l The target of methanol in the eye is the retina, specifically the optic disk and optic nerve. Müller cells and rod and cone cells are altered functionally and structurally, because cytochrome oxidase activity in mitochondria is inhibited, resulting in a reduction in ATP.


Stages of methanol poisoning:


Antidote therapy in methanol intoxication:

l Ethanol and the ADH inhibitor, fomepizole, are used as antidotes in methanol intoxication. They effectively block the metabolism of methanol and reduce its toxic effects

l Sodium bicarbonate is usually given I.V. to correct severe acidosis, and it may enhance renal formate excretion.

l Metabolic blockade is usually achieved with ethanol or fomepizole, both acting as effective competitive inhibitors of ADH.

l Folate or folinic acid (activated folate) therapy is also indicated to enhance the metabolism of formate.


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Week #4Toxic effects of solvents and vapors

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