Toxic & Health Effects

1. Principles of Toxicology
• 60,000 chemicals are sold in the US
• 8600 food additives
• 3400 cosmetic ingredients
• at least 35,000 pesticides!
• annual SOC production grew from ~20 billion lbs in the 40s to ~400 billion in the 70s (production has more or less levelled off or even decreased slightly since 1970)
• only about 2% of commercially important chemicals are known to be harmful
• however, according to the National Academy of Sciences, less than 10% of ag-chems and 5% of food additives have been fully tested to assess long-term affects
• testing is costly, time-consuming, and sometimes misleading
• as many as 1000 new chemicals are introduced to the marketplace each year
• DOT stats show ~6500 accidents each year during transport of toxic waste
• about 300 dead or injured
• accidents in the workplace are considerably more common
1. Biological effects of toxins
• immediate vs delayed toxicity
• immediate effects can be mild or severe
• usually the effects appear during exposure and disappear shortly after exposure ceases
• caused by exposure to high concentrations within a short period of time
• delayed effects may follow exposure by many years
• these are usually serious and long-lasting, such as cancer or birth defects (would we notice mild effects that followed exposure by a number of years?)
• delayed effects may result from long-term exposure to low concentrations or from short-term exposure to higher levels
• reversible vs irreversible toxic effects
• the body is able to repair the damage due to some toxic substances (in some cases there is only disturbance rather than damage) once exposure stops; such effects are considered reversible
• reversibility depends on the type of substance
• the level of exposure
• the duration of exposure
• some exposures cause permanent damage (eg death)
• local & systemic toxic effects
• local effects are effects at the site of exposure (eg rashes, eye irritation, coughing)
• systemic effects are seen at tissues, organs or organ systems remote from the site of exposure (eg brain damage, liver damage)
2. Mechanisms of toxicity
• there is a wide variety of biological actions exerted by toxins; generally, a substance is toxic because of its effects on cellular biochemistry or physiology
• enzyme inhibition, stimulation or destruction
• heavy metals bind to and inactivate enzymes
• many pesticides inactivate enzymes in nerve endings
• receptor or other macromolecular binding
• CO binds to and inactivates hemoglobin
• stimulation of chemical messengers
• carbon tetrachloride stimulates epinephrine production
• damage or destruction of DNA
• mutations can cause cell death, cancer, birth defects
3. Factors affecting toxicity
• people can react differently to exposures to the same substance; a variety of factors will shape the response
• dose
• in general, higher doses elicit more biological effects
• the role of dose is summarized in a dose-response curve
• different substances are compare by comparing the LD50 (or the ED50 for sublethal effects)
• one of the most poisonous substances known is the circular peptide produced by Clostridium botulinus; this substance has an LD50 of 10 nanograms per kilogram!
• nicotine has an LD50 (acute exposure) of 1 mg/kg; morphine, 900 mg/kg
• duration
• acute exposures are typically less than 24 hours
• chronic exposures are long-term or repeated; typically 3 months or more
• the effect of acute vs chronic exposure can be very different
• benzene has potent carcinogenic effects; chronic exposure can cause leukemia
• acute exposure, on the other hand, has psychological effects (depression)
• biological activity
• the role of biological activity can be complex
• substances which are biochemically inert are typically nontoxic (what difference would there presence make?)
• exceptions are substances which have harmful physical effects such as asbestos or radionuclides
• these substances may be more harmful because they might have a long half-life in the body
• route of exposure
• inhalation is a fast route into the bloodstream
• ingestion is a slower route
• dermal absorption is the slowest
• age
• the young of a species are usually changing the fastest and so often show the greatest effects from toxic exposure (certainly this is true of young humans exposed to lead)
• the elderly may also be more susceptible
• health status
• generally, healthier individuals are less susceptible to toxic effects
• lifestyle variables such as smoking, nutrition, stress, hygiene, etc can make a dramatic difference
• chemical interactions
• additive response: 1 + 1 = 2; there is essentially no interaction
• synergism: 1 + 1 = 3; drugs are famous for this effect, barbiturates and alcohol affect different sites on the same receptor complex
• potentiation: 0 + 1 = 3; isopropyl alcohol is relatively nontoxic but greatly increases hepatotoxicity of carbon tetrachloride
• antagonism: 2 + 4 = 3 (particulates may reduce the effects of anesthetics, though no one knows why)
• previous exposure
• tolerance: repeated exposures have smaller effects
• sensitization: repeated exposures have greater effects
• formaldehyde
• methylene chloride is a cardiac sensitizer in some individuals
4. Bioaccumulation & biomagnification
• bioaccumulation is the buildup of chemicals within the body due from a combination of factors
• resistance to breakdown: metals, chlorinated hydrocarbons
• slow rates of excretion: protein binding by metals, fat solubility
• selective absorption: metal uptake by shellfish
• lead shot now banned for duck hunting due to bioaccumulation in surviving birds
• biomagnification is the increase in a chemical as it travels up the food chain
• when eating animal products, humans see biomagnification on the order of 100,000
• fish eating birds may have tissue concentrations of DDT 10⁶ times higher than in seawater
2. Mutations, Cancer, Birth Defects
1. these can result from genetic damage caused by exposure to toxic chemicals
• mutations
• changes in genetic material, these can take several forms
• changes in DNA (base-changes or frame-shifts)
• chromosomal changes (deletions or rearrangements)
• missing or extra chromosomes
• occur naturally at a fairly high rate but are corrected by cellular mechanisms
• can be induced by chemicals or radiation (UV, xrays)
• when mutations are not repaired they are usually fatal to the cell; nonfatal mutations result in altered cellular offspring
• in a somatic cell (most of the body, produce diploid progeny cells) a mutation can cause a transformation in the cell that leads to cancer
• in a germ cell (the gonads, produce haploid progeny) the result can be a genetically defective zygote leading to miscarriage, birth defect or childhood cancer
• cancer
• the second largest cause of death in the US, it kills 500,000 people each year (at least 142,000 are tobacco caused lung cancers; ~16,000 from workplace exposure to carcinogens, ~12,000 from household exposure to radon, ~8,000 from food additives and household exposure to other chemical carcinogens, ~8,000 from ambient environmental exposure to carcinogens)
• the uncontrolled proliferation of cells
• the initial mass is called the primary tumor
• cells from this colony may break off and migrate to form secondary tumors elsewhere in the body (metastasis)
• basically, cancer results from the conversion of a single cell from normal growth to uncontrolled growth
• rapidly dividing cells such as bone marrow, epithelial tissue, ovaries, testes, are most likely to undergo the transformation
• the actual cause of cancer is not fully understood; but it does appear that the process has two components:
• conversion
• DNA mutation brought about by a chemical, physical or biological agent called a carcinogen or cocarcinogen (90% of chemical carcinogens are also bacterial mutagens)
• the mutation occurs in some gene that controls cell division
• development & progression
• the converted cell is often held in check by surrounding cells or may be destroyed by the immune system
• the uncontrolled growth of a converted cell may be encouraged by a chemical promoter or by further errors in DNA replication
• traditionally carcinogens were simply thought of as chemicals which altered DNA; there appears to be substances which cause cancer but which do not react with DNA; such substances are called epigenetic carcinogens
• hormone imbalances that promote cell growth
• immune suppression
• asbestos fibers may promote cancer by physically slicing the chromosomes of dividing cells
• there is a growing body of evidence that psychological factors may play a role in cancer (as they do in heart disease)
• those who suppress emotions have been found to be more than ten times as likely to develop cancer as those who vent emotions (as with heart disease, a causal relationship will be hard to establish)
• birth defects
• a birth defect is a structural, biochemical, or functional abnormality present at birth
• present in 7-12% of US babies, although probably half are minor
• can be caused by drugs, radiation, viruses, environmental chemicals
• these agents are called teratogens
• prenatal development has three phases:
• development and implantation of the zygote
• embryonic development=organogenesis
• fetal development=growth
• teratogens generally exert their influence during organogenesis
• the CNS and heart most sensitive in weeks 3-5
• the limbs, weeks 4-7
• dose-response, and other toxic variables can be seen in the effects of teratogens
• reproductive toxicity
• some toxins affect the reproductive abilities of men and/or women, in severe cases causing sterility; other substances can lead to increased rates of cancer or other disorders in offspring of exposed parents
• VOCs promote infertility in men
• cadmium, mercury, borax and many anticancer drugs are toxic to the reproductive systems of m & w
• maternal ingestion of diethylstilbestrol (DES) was linked to cancer in female offspring; reproductive abnormalities observed in male and female offspring
3. Controlling Toxic Substances
1. Federal laws
• Toxic Substances Control Act of 1976
• premanufacture notification for new chems
• restriction or study
• inventory and study of existing chems
• restrictions on known hazardous substances (eg, PCBs
2. Market incentives: use market forces (money) rather than regulations to reduce toxic substances
• CA’s Safe Drinking Water and Toxics Enforcement Act of 1988
• state is required to set acceptable levels for potential toxins in various consumer products and foods (state set more stds in one year than EPA has in a decade)
• if a product exceeds safe standards it must be labelled
• other types include:
• pollution taxes
• tradable permits a la CAA Title IV
3. Multimedia approach: toxic substances have often been shunted into whatever environmental medium was least regulated (eg, wastewater)
• William Reilly (EPA administrator under Bush) urged a multimedia approach to inspection and auditing
4. Determining the Risks
• life involves risk (birth is fatal)
• some are avoidable, some less so
• some have desirable benefits associated with them, others less so
• Risks & Hazards
• we often differentiate between
• natural hazards: tornadoes, floods, volcanoes, etc
• anthropogenic (human-made) hazards
• the distinction is usually not clear cut: human activities usually worsen to effects of natural events and sometimes vice versa
• Risk assessment
• two components:
• hazard identification: just what it sounds like
• estimation of risk also has two parts:
• determining probability
• determinin severity of harm
• we know that toxic chemicals can be hazardous because we see the tragic effects of high level exposure, but how do we assess risk to the general public of "routine" exposure?
• number of people exposed
• levels of exposure
• duration
• individual differences: health, habits, etc
• not practical or ethical to do human toxicological experiments, instead we use animal models (rats, mice, rabbits, college students, lawyers....)
• extrapolation to humans from other animals is not simple since the physiology of each organism is qualitatively different
• other factors of real world exposure are difficult to include in lab studies:
• interactions, very long term exposures, etc
• thresholds, non-linear dose responses
• Risk management & decisions about acceptable risk
• the notions of safety vs danger might be more accurately thought of as low vs high risk (as we said, life is inherently unsafe)
• decisions about risk sometimes involve an explicit comparison of risk and benefit, sometimes the comparison is not explicit (see table)
• in terms of public acceptability, the comparison is between perceived harm or risk and perceived benefit
• you have a 1-2% chance of dying in an auto accident yet we spend a substantial fraction of our entire income on cars; no one has ever been injured by Red Dye #2 yet it is outlawed (see Table 17-2 on page 391 of Nebel)
• for pollution, the trade off has traditionally been between pollution control and economic growth (fortunately, this tradeoff is not set in stone: the transition to a sustainable economy will require/facilitate tremendous economic expansion)
• Actual vs perceived risk: these must be close for effective policymaking
• education and communication is crucial
5. The variety of standards or ways of balancing risk and benefit might be summarized as follows:

Probability=>	Risk Assessment	<=Severity
	Is the risk acceptable?
Cost/benefit: acceptable if benefits outweigh costs	| <======|======>                 |                 |                 |                 | <=============>	Expressed preferences: acceptable if people expressly accept the risks
Natural standards: acceptable if risk is not greater than natural background		Revealed preferences: acceptable if risk is not greater than those generally tolerated

6. Cost Effectiveness (Chap 23 in Nebel)
• this is related to risk/benefit analysis
• the harm and benefits are quantified in dollars, as are the direct costs of implementing a policy or program
• difficulties in putting a price on:
• human life and health
• can use expressed and revealed preferences
• wildlife
• scenery
• biodiversity
• the timing of costs and benefits do not exactly coincide (Fig 23-11 on p 570 of Nebel and Wright, Environmental Science): short term savings must often be forgone for long term gains
4. Asbestos
1. natural silicate fibers with many useful properties
2. airborne fibers become trapped in the lungs, essentially forever; in the lungs they cause three disorders:
• pulmonary fibrosis (or asbestosis):
• the buildup of scar tissue in the lungs
• develops over 10 to 20 years of inhalation
• makes breathing impossible
• lung cancer
• can increase even with relatively short-term, low level exposure (thought to be a no-threshold phenomenon)
• lung cancer rate among asbestos workers is 4x the expected rate
• smokers who work with asbestos show a lung cancer rate 92x that of workers who don’t (~10x dif in nonworkers)
• mesothelioma
• apparently caused only by asbestos
• cancer of the mesothelium of the lungs
• generally kills within one year of diagnosis
• have been seen after only brief exposure
3. how asbestos causes cancer is unknown:
• moving DNA from interstitial space into cells?
• physically breaking chromosomes?
4. asbestos workers exposed in the US since WWII are ~8 to 11 million; cancer rate in this group is about three times that in the general populace
• approx 2M asbestos workers expected to die of cancer from 1990 to 2010
5. controls:
• banned in 1974 for use in insulation, fireproofing, and decorations
• in 1979, EPA started helping schools identify friable (crumbling) asbestos
• in 1989, EPA initiated a ban on almost all uses of asbestos, originally slated to take effect in ‘97; speeded up then slowed down by courts; "voluntary" phase out seems to be going strong
5. Mineral cycles-Toxic metals
1. Toxic Metals
• mining and processing wastes can contaminate air, water, land
• heavy metals accumulate in sediments
• disposal of dredge spoils is regulated since it is potentially hazardous
• sediments are an active source/sink of HMs in the environment
2. Mercury cycle
• elemental mercury is a liquid, insoluble under anaerobic conditions, relatively harmless since it is not bioavailable (some folks drink the stuff to ward off evil spirits)
• at the interface of aerobic and anaerobic conditions
• mercury sulfide can form
• converted to mercury sulfate then to methyl mercury which is bioavailable and extremely toxic
• neurological symptoms but damage to all organs
• hat makers worked with vats of mercury compounds (used to keep the mold from growing on the wet felt) and went crazy, hence the term "mad as a hatter"
• long half-life in the body (70 days)
• mercury has widespread as a toxin, catalyst, and conductor
3. Lead cycle
• metal widely used for its density, low melting point, and malleability; lead also can be used to form a variety of pigments and was used as an anti-knock compound in gasoline until very recently
• lead is extremely abundant due to its former use in gasoline
• lead 100 times more abundant in heavily traveled areas
• 98% of atmospheric lead from autos
• lead poisoning symptoms: listlessness, fatigue, impaired mental function, loss of IQ, brain and other organ damage, death
• according to the CDC, lead-poisoning is the number one preventable illness of childhood in this country (primarily due to lead in paint since the removal of leaded gasoline); many lead-poisoned children suffer irreversible IQ loss
4. cadmium
• cadmium salts are used primarily as yellow pigments
• the color of CdS depends on the size of the particles, so a wide range of hues can be made
• Van Gogh’s "Sunflowers" utilize CdS pigments (some say the cadmium drove him crazy)
• CdS and CdSe are widely used to color plastics
• cadmium is also used to plate steel
• cadmium is often present as a contaminant in zinc (it is below zinc in the periodic table and often occurs in ores containing zinc)
• cadmium is considered to be a volatile metal when heated
• can be acutely toxic; (LD is about 1 g)
• although you probably could not eat a gram of cadmium salts (they would make you violently sick to your stomach; you might be able to breathe in enough cadmium vapor to kill
• cadmium is complexed by metallothionein, a protein that usually regulates zinc metabolism
• low levels get excreted in the urine, high levels accumulate in the liver and kidneys
• eating liver increases dietary Cd intake (eskimos like to eat caribou kidneys)
• Cd⁺² also substitutes for Ca⁺², especially in the bones
• plants can apparently take up Cd⁺² from contaminated irrigation water
• water from the Jintsu River in Japan is contaminated by wastewater from zinc mining and smelting
• the local people develop "itai-itai" (translation: ouch-ouch) from contaminated rice
• cadmium is apparently not biomagnified by it can be persistent in the body if exposure exceeds what can be handled by metallothionein
5. chromium
• chromium has widespread industrial use; essential element for humans but toxic and carcinogenic at higher levels
6. Trace elements
• many elements have been concentrated for human to levels many times their natural abundance in the crust
• arsenic used as a toxin, in electronics, etc; poisonous
• fluorine-essential for animal life but can be hazardous at even fairly low concentrations
6. Radiation
• around the turn of the century, Roentgen, Curie, Becquerel, Rutherford, and others, explored the properties of radiation
• they found that radiation was emitted by certain substances bombarded by high-energy electrons (in CRTs) or by certain elements, which changed their atomic number in the process of emitting radiation
• they found that radiation could expose photographic emulsions or cause fluorescence
1. What is radiation?
• these observations clue us in:
• radiation is of two basic forms (though in theory they are actually overlapping)
• particles (alpha, beta, neutron)
• alpha particle is a helium nucleus (two protons, two neutrons), big but slow, can be stopped by a piece of paper, can wreak havoc on lung tissue, emitted by uranium and radon among others
• beta is a very high energy electron (much like the ones in Roentgens CRT) emitted during the process of radioactive decay, betas can be stopped by plastic or metal, though heavy metals tend to give off xrays when bombarded by betas; many bioelements have beta-emitting isotopes
• electromagnetic radiation
• gamma or xrays form an overlapping band high on the EM spectrum
• these have infinite penetrating power though shielding can reduce the overall flux
• these types of radiation are sometimes called ionizing radiation (to contrast with things like microwaves which are nonionizing)
• a photon of ionizing radiation has sufficient energy to strip an electron off an atom; this can be a problem if the atom is in your body=unhealthy chemical changes (including mutations) can result
• nuclear radiation is emitted by decaying nuclei of radioisotopes
• these have characteristic decay schemes
• the probability that a decay will occur is a fixed property, though any given atom could decay at any time
• for any sample of material, the amount present decreases according to the half-life of the material
• T½ is the time in which half of a sample of radioactive material will decay
2. Measurement of radiation
• dose units can get sort of confusing
• the basic idea is based on the amount of energy imparted to matter
• the rad is the
• the LD50 for radiation (acute exposure-whole body) is about 400 rads
• since the biological effects of radiation are dependent on the type of radiation along with some other factors, these are considered to convert rads to rems
• occupational and background exposures are typically on the order of thousandths of a rem or millirems
• average yearly exposure is about 182 mrems (102 is solar and other natural background, 72 is medical xrays)
• a posted radiation area is >2 mrem/hour
• instruments for measuring radiation typically use some scintillation material, a liquid, solid or gas which emits light when exposed to radiation; a geiger counter uses a tube that produces an electrical current proportional to incoming beta or gamma radiation
• if standardized sources are used, the level of radiation can be used to calculate that amount of radioactive material present in a sample
3. Effects of radiation
• Acute and chronic exposure
• acute refers to one time high level exposure; chronic to repeated, usually lower level exposure
• exposure to hundreds of rems causes damage to actively reproducing cells such as bone marrow (the source of blood cells) and epithelial tissue (intestines, mucous membranes), skin and other connective tissue
• if sufficient cells are left viable after exposure (typically less than ~250 rems) the victim has a good chance of surviving the acute episode
• there may still be long term effects (cancer, genetic damage)
• Somatic vs genetic effects
• somatic means "pertaining to the body"; somatic effects are effects on the tissues and organs of the exposed animal
• genetic effects are the result of mutations induced by ionizing radiation
• the NRC estimates that exposure to as little as 5 rems (this is the yearly occupational exposure limit, but the NRC is talking about a single dose) can cause an increase on the order of one percent
• about one fifth of the damage is seen in the first generation
• effects can linger for many (30+) generations
• Cellular effects
• caused by ionization of water or cytochemicals
• ionized species may malfunction or damage other molecules
• Effects on whole organism
• general patterns of change typical of species, age, and type of exposure
• more complex animals, such as mammals, tend to show greatest sensitivity
• insects (adults) can withstand more rads than vertebrates; unicelled creatures relatively resistant
• in humans:
• birth defects are dependent on tissue undergoing development at time of exposure
• acute effects mentioned above; blindness (cataracts), sterility, leukemia
• other cancers (breast cancer seems more easily induced by radiation, for some reason)
• cancer caused by a wide variety of agents, mechanism is not known, though any mutagenic agent is suspected as a carcinogen; cancer cells have somehow been induced to grow uncontrollably
• there are correlations in exposed populations
• why can radiation be used to treat cancer?
• Effects on populations & communities
• can alter the reproductive abilities of populations (maybe we should feed N-waste to deer???) and perhaps even the gene-pool; the levels discussed in the book are only likely in event of nuclear bombing or disaster or locally with radioisotope contamination of a food supply
• microbes living in "hot" habitats seem to be more resistant to the effects of radiation
4. Sources of Radiation
• Atmospheric sources (approx 40 to 130 mrem per year)
• there are two different sources of radiation from above:
• decay of radioisotopes within the atmosphere
• solar radiation (cosmic rays)
• the lower atmosphere shields somewhat against both, hence there is more radiation at higher elevations (like in CO or in an airplane)
• cosmic radiation is more intense at higher latitudes
• Terrestrial sources
• naturally occuring radioisotopes (including K-140, uranium and its progeny) in the bedrock and soil
• provide about 15 to 140 mrem per year
• areas with uranium mine tailing have considerably higher levels (up to 200 mrem/year)
• Uses of radiation and radioactivity
• diagnostic and therapeutic x-rays
• biological and biochemical research
• nuclear fuel
• nuclear weapons
• atmospheric testing produces fallout=radioisotopes spread by wind and weather around the world
• irradiated food, kills germs and fungi (is it safe?)