Toxiology

Lecture 9

Transport

* movements of contaminants within or between environmental media

Fate

* physical, chemical or biological transformations of contaminants in the environment

Fate

and transport of chemicals is affected by their physical-chemical properties

Harmful

a substance is depends on physical-chemical properties of the substance

Volatility

Physical-chemical Properties

Polarity

Physical-chemical Properties

Solubility

* Water soluble toxins
* –  Fat soluble toxins (Lipophilic tendency)
* Physical-chemical Properties

Oxidation state

Physical-chemical Properties

Molecular weight

Physical-chemical Properties

Bioaccumulation

building up over time, in individual organisms

• Consequences of lipophilic tendency

Physical-chemical Properties

Biomagnification

building up over time, across the levels in a food chain

• Consequences of lipophilic tendency

Physical-chemical Properties

Physical-chemical Properties

Generally, higher-molecular-weight chemicals are:

– More lipophilic and more persistent – Less volatile and less water-soluble

Persistence in environment \n – Quantified as a half-life in air, water, or soil – Affected by environmental conditions

Toxicology

the science of the effects of toxic substances and of their fate and transport in the body

* “Study of poisons”
* “the science which studies toxic substances or poisons, that are substances which cause alteration or perturbation in the function of an organisms leading to harmful effects (Truhaut, 1974)
* Receptor
* Exposure
* Dose
* Response

Receptor

* Organism (human?) receiving exposure or dose
* The human envelope—boundary that separates the interior of the body from the exterior environment
* Age
* General health
* Genetic makeup \n

Exposure

* Contact with the human envelope

Routes of exposure

* –  Ingested (often greatest source of chemical exposure, 85%)
* –  Inhaled (air pollution, particles and volatiles, 10%)
* –  Absorbed through the skin (industrial, 5%) • Frequency of exposure

Exposure Assessment

• Goal is to quantify exposure

(or to find out Dose) \n • Methods draw on understanding of both:

– Environmental science (fate and transport of toxicants in environment)

– Toxicology (fate and transport of toxicants in the body)

Completing the Conceptual Model of Exposure

a) source: emission or concentration in ambient environment------1)false and trasnport-------b)concentration in microenvironment or personal environment------2) ingestion, inhalation, dermal contact.

Toxicoknetics

the disposition of toxicants in the body

Completing the Conceptual Model of Exposure Toxicokinetics

c) exposure----d) absorbed dose-----e0 biologically effective dose-----f)change in tissue structure of function------g)possible health effect

Quantifying Exposure

Tools for area monitoring and personal monitoring

**Area monitoring**

A filter inserted into the nozzle of a vacuum cleaner (a) collects dust to be analyzed in a laboratory. \n

**Personal monitoring**

A portable sampling device (b) incorporates a pump that takes a continuous air sample near the subject’s breathing zone; the device also collects a sample of particulate matter over the whole period.

Units of absorbed dose: mg / (kg\*day)

– Mass of toxicant \n – Normalized to body weight \n – Averaged over time

Quantifying Exposure

Other sources of exposure info

* –  Questionnaires, diaries
* –  Surrogate measures (measure of effect of a specific treatment that may correlate with a *real)*
* –  Geographic information systems (GIS) \n Quantifying Exposure

A quantification of exposure

the amount of substance a person has ingested inhaled or/and absorbed

Dose

Acute dose

refers to single dose, usually high

Dose

Chronic dose

repeated or continuous low dose over time

Dose

Long term

low dose over a lifetime

Dose

Body burden

– Absorption – Distribution – Metabolism – Storage

– Excretion

Toxicodynamics

effects in the body (response)

Burning

destruction of cells caused by exposure to high concentration of strong acids or bases

Response and Nonspecific

Narcosis

depression in sensory activity, reversible, caused by alcohols, ethers, and benzene

Response and Nonspecific

Specific

* Damage to excretory organs
* Damage to respiratory organs
* Damage to reproductive function
* Mutagenesis
* Carcinogenesis
* Response

Acute toxicity

rapid death

Response

Chronic toxicity

Response

Paracelsus’ Principle: *“The Dose Makes the Poison”*

• Every chemical is harmful at some level of exposure

• How much exposure causes a harmful response????

* Differently for different individuals
* The dose of a usually unknown mixture of chemicals

The Dose-response Relationship

• Quantitativerelationshipbetweendoseandeffect

(response)

– Often summarized in graph \n – Dose on x-axis; response on y-axis \n – Graded response as a function of dose – Acute toxicity tests are used

Slope

(potency of effect) and Dose- Response Curves (more potent and less potent) response relationship

Threshold

(potential for safe dose) and response relationship (b and a separate)

Dose- Response Curves

S-Shape

• A more realistic flattened *S*-shape

a) slope looks like one stair going up

b) threeshold looks like two stairs going up

Toxicity Testing

• Chronic rodent bioassay (2 years)

– 3 exposure levels, ideally including: \n • Dose high enough to test for cancer \n • Dose low enough to reveal no-effect level

– Unexposed control group \n – Results used to create dose-response curves for

various health effects

*Highest*

non-zero dose at which *no* effect was observed = No Observed Adverse Effect level (NOAEL)

* Toxicity Testing

*Lowest*

dose at which an effect *was* observed = Lowest Observed Adverse Effect Level (LOAEL)

* Toxicity Testing
* If a study shows both a NOAEL and a LOAEL, can infer that the threshold is between them

Two dose-response curves

a) dose-response curve showing NOAEL and LOAEL

b) dose-response curve showing only LOAEL

curves

Dose-response curves developed for cancer and various non-cancer effects

*Reproductive* toxicity

effect on reproductive capacity

of organism

*Developmental* toxicity

effect on developing organism, including teratogenesis

Other Methods for Toxicity Testing

• Case reports

• Epidemiological studies \n • Computer simulations \n • Tissue cultures of cells and bacteria

**Endpoint**

physiological manifestation

– Can be readily measured

– Use of “biomarkers” e.g. changes in hormone levels, protein markers, and enzyme induction

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Measuring Manifestations