Readings: Chapter 3 in Hill
http://www.sis.nlm.nih.gov/Tox/ToxTutor.html

ENVIRONMENTAL HEALTH and TOXICOLOGY

With makers of products found on grocery store shelves and cosmetic counters jumping on the bandwagon and touting the "all natural" ingredients they use in an effort to lure more buyers, it is tempting for consumers to assume that natural products, ingredients, and processes are inherently safer and healthier than synthetics or artificially manufactured ingredients. Yet we are exposed to thousands of chemical compounds through air, water, and food, and source of origin is no reliable indicator of safety or toxicity. Foods artificially fortified with vitamins, minerals, and antioxidants may be nutritionally superior to their "all natural" counterparts; and, one of the most potent carcinogens around, aflatoxin, is produced by a naturally-occurring fungus that grows on grains and peanuts.

Our fears of toxins and pollutants often do not coincide with the actual risks they pose. How do we identify the real environmental and human health risks associated with the myriad chemicals we consume and dump into our environment? Obviously, many subjective factors are involved, and there is no way to make absolute, objective judgments as to the satisfactory regulation of these substances.

Human health problems and disease are often indirectly related to environmental conditions; direct causal relationships, though, are difficult to establish. Not all environmental conditions harmful to our health are human-caused; there are many forms of natural pollution and toxins.

Table 3.1

Which of the following substances would you consider to be a problem?

Milk
Aspirin
Warfarin (rat poison)
Fluoride

Table 3.2

Environmental concentrations of pollutants are often measured in parts per million or parts per billion, representing a percentage of total volume or weight.
Water pollution may be measured in milligrams or micrograms per liter; air pollution is commonly measured as micrograms per cubic meter.

Acute and Chronic Effects
Acute – death in a short time
Chronic – death resulting from a prolonged exposure

How to determine toxicity
A very large and significant environmental problem
4.3 million chemicals in use
1000 new per year
Tests are very expensive -$500,000-800,000/compound

Table 3.4

Dose Response
The dose-response relationship is a fundamental and essential concept in toxicology.  It correlates exposures and the spectrum of induced effects.  Generally, the higher the dose, the more severe the response.  The dose-response relationship is based on observed data from experimental animal, human clinical, or cell studies.

The Dose-Response Curve
The dose-response curve plots the effect of a substance against exposure of the affected population.
The dose at which 50% of exposed subjects show non-lethal response to a toxin is the ED-50; the dose at which 50% of exposed subjects die is the LD-50. LC50 (often used for toxics in air or water)

ED typically used for drug therapy not toxicants

Threshold Effects
A threshold is a level below which no effect is detected and above which effects are detectable.
Very hard to determine, particularly for carcinogenic substances, long-time frame
While thresholds are often used in determining allowable levels of human exposure to individual toxins, they do not take into account the synergistic effects of the many toxic pollutants we are exposed to.

Descriptive terms:
NOEL or NOEC - no observable effect level or concentration
LOEL or LOEC - lowest observable

Anatomy and Physiology
General concepts:
· Cells heterogeneous - many reactions are occurring at the same time
· Low energy gradients - reactions very slow unless catalyzed
· Many reactions depend on specific catalysts
· All reactions of two types - anabolism and catabolism
Catabolism - breakdown of products to release energy
(respiration, breakdown of proteins, lipids, carbohydrates)
Anabolism - synthesis of new materials, requires energy
(synthesis of proteins, fats, etc.)

Three phases of toxicant action: routes of exposure or uptake, toxokinetic, toxodynamic
(ADME in text) Adsorption, distribution, metabolism, excretion

Exposure- the movement of a contaminant into an organism
oral, parenteral, inhalation, percutaneous
Can involve the dermis, gills, pulmonary surfaces, or gut

Percutaneous outer layer forms a barrier but is permeable, oil-based substances pass more easily
some substances such as alcohol increase permeability'
Inhalation -A major entry point for environmental toxicants

Toxokinetic - factors influencing how much of a toxicant reaches target tissue
Uptake and distribution, metabolism, retention (bioaccumulation), excretion

Absorption (uptake)
passive diffusion – determined by the size and shape of molecule, charge on molecule, pH, lipid solubility, move across concentration gradients
active transport – requires a source of energy, ATP, and carrier proteins, very important in nerve conduction (Na-K pump)

Another important factor is the concentration of the exposure

Distribution is the process whereby an absorbed chemical moves away from the site of absorption to other areas of the body. 

Once a chemical is in the blood it may be: excreted, stored, biotransformed its biotransformation products may be excreted or stored, the chemical or its products may interact or bind with cellular components

Biotransformation
iologically-mediated transformation of one chemical compound for another
detoxification
bioactivation

· Can be converted to a more hydrophilic form helping in elimination
· Can be rendered less toxic
· Can be transformed and sequestered

Metabolic reactions
metabolism - biotransformation - degradation

(oxidation reduction, hydrolosis),
conjugation (chelation, methylation, acetylation)

Excretion - most by kidney, may be excreted by liver into bile, respiration or sweat

Hydrophilic substances are favored over fat (lipid)-soluble toxicants as regards elimination from the body.
The main routes of excretion are via urine, feces, and exhaled air.  Thus, the primary organ systems involved in excretion are the urinary system, gastrointestinal system and respiratory system

Retention - accumulation and storage, affect longevity of action, may be available if processes change
Accumulation - net accumulation of a contaminant in or on an organism from all sources
Bioconcentration - a more restricted term used for contaminants accumulated from water only

Factors Affecting Toxicity
The physical properties of the contaminant affect its bioavailability (the extent to which a contaminant in a source is free for uptake) - these are described by SARs-structure activity relationships
Developmental (age) and sex-related factors
Ecological and behavioral qualities of an organism (nutritional status, eating habits)
Environmental conditions -Temperature, salinity, pH

Selective toxicity refers to species differences in toxicity between two species simultaneously exposed. 
Table 3.5

Antogonism, synergism

How can toxokinetics influence toxicity?

Toxodynamic - interaction between toxicant and specific tissue
· interference with enzymes
· uncoupling agents (interfere with synthesis of ATP, energy lost as heat)
· interference with photosynthesis
· lethal synthesis (fluoracetic acid converted to fluorcitric instead)
· removal of essential metals
· inhibition of oxygen transfer
· interference with DNA and RNA synthesis (carcinogens, mutagens)
· hypersensitivity reactions (results from formation of antibodies)
· direct irritation of tissues

Systemic Toxic Effects Toxic effects are generally categorized according to the site of the toxic effect.  In some cases, the effect may occur at only one site.  This site is referred to as the specific target organ.  In other cases, toxic effects may occur at multiple sites.  This is referred as systemic toxicity.  Following are types of systemic toxicity:

Acute Toxicity
Subchronic Toxicity
Chronic Toxicity
Carcinogenicity
Developmental Toxicity
Genetic Toxicity (somatic cells)

Epidemiology
The science concerned with the cause, incidence, prevalence, and distribution of infectious and noninfectious diseases in populations.

Epidemiology studies are conducted using human populations to evaluate whether there is a causal relationship between exposure to a substance and adverse health effects.Epidemiological studies measure the risk of illness or death in an exposed population compared to that risk in an identical (e.g., same age, sex, race, social status, etc.), unexposed population

There are four primary types of epidemiology studies.  They are:
Cohort studies
Cas-control studies
Cross-sectional studies
Environmental studies

Aspects of disease association
Strength of association
Consistency of association
Specificity of association
Temporal association
Dose-response
Biological plausibility
Experimental support
Analogy

Effects
General population response - changes in number of individuals - easy for an outbreak
Demographic change - changes in birth rate- death rate
Population genetics
acquisition of tolerance (insect pests)
genetic drift

Community Effects of Toxicants

Effects on keystone species
Most sensitive species approach

Effects
Predation and grazing
Competition

Measures
Species richness/diversity
Trophic composition
Abundance and condition
Often done in micro or mesocosms or biomonitoring

Group B Assignment

pg 51 of your text has a quote from a Harvard epidemiologist.

Below is a link to a story on CNN and the article which engendered the story. Were the results of the study reported accurately? Using the criteria in your text p.51-52 for judging a study, were the results sensationalized or not.

http://www.cnn.com/2004/HEALTH/01/09/smoking.ap/index.html

http://bmj.bmjjournals.com/cgi/content/full/328/7431/72

I have hard-copy if they are not still available.

Due 1/29/04