Basic Toxicology

BASIC TOXICOLOGY The harmful effects of chemicals on biological systems

DEFINITIONS TOXICITY - the capacity of a chemical agent to cause harm when absorbed into the body. HAZARD - the toxicity, and the probability that the chemical agent will be absorbed and cause harm under a specified set of conditions. Note that under some conditions of use a very toxic chemical may represent a smaller risk or hazard than a less toxic compound.

MEASUREMENT OF TOXICITY DOSE-RESPONSE RELATIONSHIPS The Dose-response relationship is a measure of the number of individuals in a large group of subjects which show a particular effect at a specific level of exposure (dose).

The Dose-Response Relationship 70

Response

60 50 40 30 20 10 0 -3σ

-2σ

-1σ

µ

Dose

1σ

2σ

3σ

ACUTE TOXICITY - ANIMAL STUDIES The starting point in evaluation of toxicity of a chemical is the determination of lethality (LD50) LD50 - the dose that is estimated to kill 50% of a group of animals after one dose or short exposure. LC50 - the concentration (in air) of the agent estimated to kill 50% of the test animals after one short exposure by inhalation.

LD50 is used as a method of comparing acute toxicities of different chemicals. Because it only deals with one endpoint, death, it cannot reveal anything about the chronic effects or other toxic effects of the chemical.

TYPICAL TOXICITY CLASSIFICATION BASED ON LD50 1. Extremely toxic 2. Highly toxic 3. Moderately toxic 4. Slightly toxic 5. Practically non-toxic 6. Relatively harmless

1 mg/kg or less 1 - 50 mg/kg 50 - 500 mg/kg 0.5 - 5 gm/kg 5 - 15 gm/kg more than 15gm/kg

Some Approximate Acute LD50s Agent § Ethyl alcohol § Sodium chloride § Ferrous Sulfate § Morphine sulfate § DDT § Strychnine sulfate § Nicotine § Tetrodotoxin § Dioxin § Botulinus toxin

LD50 (mg/kg) 10,000 4,000 1,500 900 100 2 1 0.1 0.001 0.00001

Comparison of Dose-Response Curves 50

Response

40

30

A

B

20

10

Dose

Comparison of Dose-Response Curves 50

Response

D 40

30

20

10

C Dose

SELECTIVE TOXICITY Toxicological testing with animals is complicated by the fact that different species respond differently to the same chemicals. This may be due to: 1. 2. 3. 4.

differences in surface area differences in accumulation differences in rate of biotransformation differences in biochemical pathways

MALATHION (relatively inactive)

rapid - insect rapid - mammal

slow - insect rapid - mammal

Oxidation (microsomal enzymes)

hydrolysis and binding

PRODUCTS (inactive)

MALAOXON (active) hydrolysis (A - esterases) slow - insect rapid - mammal

TOXIC EFFECTS Local vs Systemic toxicology Local - Irritant chemicals when inhaled produce local toxic effects in the lungs. e.g. HCl, NH3 Systemic Toxicity - Many toxic substances affect a number of organ systems well removed from the site of absorption. Usually one or two organs will suffer the greatest toxic effect. These are the target organs for the toxicant.

Immediate vs Delayed toxicity Immediate - HCN, CO, H2S Delayed - phosgene, tri-orthocresyl phosphate Long Latency - carcinogenic compounds, often have a latency period of 20-30 years

ACUTE vs CHRONIC EXPOSURES ACUTE - a single exposure or several exposures over a short period of time

CHRONIC - repeated or continuous exposure over a long period of time

ACUTE vs CHRONIC EFFECTS Acute effects require higher concentrations of the agent and are usually different from the effects produced by chronic exposure e.g. Lead - colic with acute exposure - wrist drop with chronic exposure

FREQUENCY AND DURATION OF EXPOSURE

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Frequency and duration of exposure is important if some detoxification or elimination of the agent occurs between exposures.

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Two consecutive 12 hour workday exposures to a chemical are not equivalent to three consecutive 8 hour workday exposures.

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An important consideration when applying exposure levels designed for workers working an 8 hour shift to graduate students.

CLASSIFICATION OF TOXICANTS 1. Irritants a. primary b. secondary 2. Asphyxiants a. simple b. chemical 3. Narcotic agents 4. Hepatotoxic agents 5. Nephrotoxic agents

6. Neurotoxic agents 7. Hematopoietic toxicants 8. Fibrogenic agents 9. Sensitizing agents 10. Mutagens 11. Carcinogens 12. Teratogens

ABSORPTION Laboratory chemicals may be absorbed 1. Through the lung 2. Through the skin 3. Through the gastrointestinal tract

MECHANISMS OF TOXICITY Absorbed chemicals may act as systemic toxicants throughout the body, or may attack specific target organs. Differences in mechanism are due to: 1. Differences in ability to cross cell membranes 2. Solubility differences in different tissues 3. Blood supply to specific tissues 4. Differences in chemical reactivity

BIOTRANSFORMATION • chemical transformations of a foreign chemical in an organism

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chemical may be made more toxic, or less toxic

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but, methyl alcohol is oxidized by the same enzyme system to formaldehyde - more toxic than the alcohol.

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rate of these metabolic transformations varies between individuals and between species

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accounts for SELECTIVE TOXICITY.

e.g. ethyl alcohol is detoxified by oxidation to the acetyl group which enters normal cellular metabolism (the citric acid cycle)

EXCRETION The body may eliminate chemicals by way of: 1. exhaled air (the lung) 2. urine (the kidney) 3. feces (biliary excretion) 4. maternal milk 5. hair, nails 6. sweat, saliva Many toxic chemicals can also cross the placenta and enter the fetal circulation.

MEASURES OF TOXIC HAZARD The LD50 is not very useful for assessing risk of ongoing or chronic exposures. To measure the exposure hazard associated with airborne chemicals, measures based on the concentration of the chemical in air are used.

THE AMERICAN CONFERENCE OF GOVERNMENTAL INDUSTRIAL HYGIENISTS (ACGIH) Exposure Limits TLV (Threshold Limit Value) The concentration of an air contaminant to which nearly all workers can be exposed 8 hrs a day without significant adverse effect. TLV-TWA (Time Weighted Average) TLV-STEL (Short Term Exposure Limit) TLV-C (Threshold Limit Value - Ceiling)

In Ontario: TWAEV - Time Weighted Average Exposure Value STEV - Short Term Exposure Value CEV - Ceiling Exposure Value These exposure limit values should not be taken as quantitative measures of relative toxicity They do not represent a clear cut dividing line between safe and unsafe exposures They are a useful, semi-quantitative guide to the hazard presented by chemicals.

SOME EXPOSURE LIMITS IN ONTARIO TWAEV COMPOUND

ppm

acetone 500 acetonitrile 40 carbon disulfide 10 toluene 50 benzene 0.5 toluene diisocyanate (TDI) 0.005 mercury (inorganic) lead

mg/m3 1185 67 31 376 1.6 0.035 0.025 0.05

THE OCCUPATIONAL HEALTH AND SAFETY ACT In Ontario, workplace exposures to hazardous chemical and physical agents is regulated by the Occupational Health and Safety Act and a series of specific regulations made under this act.

The Designated Substance Regulations Asbestos Arsenic Acrylonitrile Benzene Coke oven emissions Ethylene Oxide

Isocyanates Lead Mercury Silica Vinyl chloride

Chemical Engineering and Applied Chemistry requires that researchers using these substances complete and post a Permit to Use a Designated Substance in their laboratories. This permit describes quantities to be used, room location and control procedures that the researcher intends to use to limit exposure. This permit is also required for the use of a number of other substances which have been designated by the department. These include: carbon disulfide carbon tetrachloride formaldehyde styrene

The End