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Toxicology and Human HealthToxicology and Human Health(Moeller Chapter 2)(Moeller Chapter 2)

Geography 361aGeography 361aEnvironment and HealthEnvironment and Health

• Context• What is toxicology?• Toxins in the body• Toxicity of chemicals• Tests for toxicity• Outcomes measured• Establishing exposure limits

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ContextContextChemicals in the EnvironmentChemicals in the Environment

• Outline some of the challenges the table below represents.

• How can we (society) address those challenges?

Author Chemicals in Existence

New Chemicals/Year

Moeller (2003) 70,000 200-1000

Philp (1995) 64,000 700

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Toxicology: Definition

• “The discipline that integrates all scientific information to help preserve and protect the health and the environment from the hazards presented by chemical and physical agents “(Society of Toxicology as cited in Moeller 2005, 28)

• (see models of health/causality from last day)

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Environmental Toxicology: Definition

• The study of the harmful effects of (combinations of) chemicals on the health of entire ecosystems.

• Used as the basis for chemical management (e.g., safe limits, priorities for cleanup)

• See Health Canada’s Chemical Substances Portal

(useful for assignment 1 too)

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Toxins into the Body

• lungs, gastrointestinal tract, skin• most toxins enter how?

respiratory system

GI tract

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Toxins in the Bodybiological transformation• metabolic process that transforms substance

so moves from one organ or tissue to another

• chemical conversion to new compound• typically less absorbable (excreted)• bioactivation

– biological transformation that forms a compound that is more toxic than the original substance inhaled/ingested/absorbed

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Toxins removed from the Body

excretion• urination – main form of excretion• lungs• GI tract, sweat glands – least important• liver and kidneys

• health of these systems can effect body’s ability to withstand toxic “insults”

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Toxins in the Body

Other biological factors influencing response• age – young and old most vulnerable• sex – particularly reproductive impacts• disease – esp. liver disease (re: excretion)

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Toxins in the Body

Environmental factors influencing response• ambient temperature (e.g. ↑ temp + dinitrophenol

herbicide = ↑ toxicity)• humidity – ↑ typically = worse• light – diurnal pattern ↑ light typically = worse• social – lab animals housed singly or in groups

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Toxicity of Chemicals

• “What is it that is not poison? All things are poison and nothing is without poison. It is the dose only that makes a thing not a poison.” (Paracelsus, 16thC, emphasis added)

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Toxicity of Chemicals

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Toxicity of Chemicals

• qualitative ranking of toxicity of chemicals

ethanol

sodium chloride, aspirin

Examples

caffeine, phenol

arsenic, strychnine

dioxin, botulinum

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Toxins in the Environment

biomagnification• up the food chain• typically accumulate in fat • heavy metals (e.g.,lead,

mercury)• organochlorine pesticides

(e.g., DDT)• PCBs

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Tests for Toxicity: Exercise

• Suggest ways that the toxicity of substances might be tested scientifically.

• What problems are involved?

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Tests for Toxicity

• laboratory – highly controlled, randomization

• animals – rats or mice typically• ethical issues

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Tests for Toxicity: Types of Studies

acute toxicity• single or multiple doses (high)• short period of time

short-term (subacute, subchronic)• repeated (daily) doses• period = 10% of animal lifespan (e.g, rat = 3mo)

long-term (chronic)• entire lifespan of animal

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Tests for Toxicity: Outcomes

• change in body weight

• growth of tumours

• change in body size

• death (typically) (see LD50)

MTD

• maximum tolerable dose

• highest dose below which cancer does not occur

• debated whether high doses exaggerate carcinogenicity (but see precautionary principle)

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Acute Toxicity Studies• some animals are more susceptible, some more resistant

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Acute Toxicity Studies

• LD50 using cumulative % curves

• Which substance is more toxic: (A) or (B)?

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Example LD50 Values

• dichlorvos, an insecticide commonly used in household pesticide strips

• Oral LD50 (rat): 56 mg/kg • Dermal LD50 (rat): 75 mg/kg • Injected to abdomen LD50: (rat) 15 mg/kg • Inhalation LC50 (rat): 1.7 ppm (15 mg/m3); 4-hour • Oral LD50 (rabbit) 10 mg/kg • Oral LD50 (pigeon:): 23.7 mg/kg • Oral LD50 (mouse): 61 mg/kg • Oral LD50 (dog): 100 mg/kg • Oral LD50 (pig): 157 mg/kg

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Acute Toxicity Studies: Summary

Benefits• death is easily measured• autopsies = info on probable target organs• determine doses to be used in longer-term studies

Drawbacks• death is only one of many possible outcomes• humans rarely exposed at such high levels

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Short and Long-Term Toxicity Studies

• typically 2 or more species (rat + dog)• animal to biotransform chemical much like human

would in real world• three dose ranges – high(won’t kill) medium

low(no expected effects)

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Longer Term Toxicity Studies: Summary

Benefits• biotransformation measured• assess acceptable intake values• NOEL – no observed effect level

Drawbacks• $$• biotransformation assumptions – different species

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Outcomes Measured

• carcinogenesis– staged: initiation, promotion, progression– some chemicals do one, two or all three

• Ames Test– in vitro test of mutagenicity to bacteria– very inexpensive– assumes mutatagenicity similar to

carcinogenicity

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Outcomes Measured

reproductive toxicity• both to parents and offspring• e.g. mother during or prior to gestation• e.g. lead or PBC – menstrual disorders

developmental toxicity (teratogenesis)• congenital effects• e.g. growth retardation, malformations• e.g. thalidomide

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Outcomes Measured

Neurotoxicity• cognitive, sensory, motor• often wide variation between rat/dog and human

responses of this type• 1000+ chemicals identified as neurotoxicants

(only 10% - 7000 - tested though)• e.g., trichloroethylene

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Outcomes Measured

Immunotoxicity• suppression of immune function• host vulnerable to infection (incl. cancer)• e.g., multiple chemical sensitivity syndrome – low

dose exposure = AIDS-like response– very controversial at this point– emerging area of research

• e.g., pcb, ddt, asbestos, benzene

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Outcomes Measured

Summary• most chemicals (only 20% of chemicals in use

today) assessed for carcinogenesis only • being revisited under USA SARA legislation• Agency for Toxic Substances and Disease

Registry (ATSDR) data base growing (slowly) as a result

• (keep in mind 99% of all toxic human exposures from “natural” environment e.g., bacteria)

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Extrapolating from High Doses

How can we know at what dose a substance is harmful or not?

This video summarizes some of the key ideas in this entire lecture, but the main theme is extrapolating from high doses:http://www.youtube.com/watch?v=IKujq-TcJLM

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Extrapolating from Animals

relative responsiveness• small animals to large humans

dose• relatively high doses for short periods of time

versus low doses over long periods of time• creates highest uncertainty and highest

controversy• e.g., what is the shape of the dose-response below

the minimum dose administered in toxicity experiments? – linear or threshold? – hormesis?

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Establishment of Exposure Limits

Two Principles (order of importance):

1. use human data whenever possible

2. use surrogate species or surrogate chemicals if scientific basis for comparability with target population

• most frequently principle 1 not satisfied.

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Establishment of Exposure Limits

Steps:• establish range of effects for target or surrogate

chemical – (chemical’s database)• establish dose-response relationship in target

species or surrogate species• establish exposure limit by adding in safety

factor

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Dose/Response Curves

• many acute effects are threshold effects• many chronic/cancer effects are non-threshold

effects

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Dose/Response Curves

• most animal studies involve medium or high doses that must be extrapolated backwards

• if “C” is limit set = “safe” according to extrapolation “B” but unsafe according to extrapolations “D” and especially, “E”

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Establishment of Exposure Limits

Safety Factor (or Uncertainty Factor – UF) of:10 (account for most sensitive human)• i.e., 10 * NOEL or threshold level• valid chronic human exposure data100 (account for interspecies extrapolation)• i.e. 100 * NOEL or threshold level• no human data• satisfactory chronic exposure data in other species1000 (account for interspecies extrapolation)• i.e. 1000 * NOEL or threshold level• chronic exposure data incomplete for other species

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“Conservative” Estimates

• precautionary principle