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Topic 2: Toxicology Concepts Environmental Challenges and Defense Systems  Discuss the 2 types of environments we have to be aware of when we're studying environmental health. How do they relate? o The two types of environment:  External environment (what we normally think of): everything that is not "us"  Internal environment (that which occurs within the individual person): because people and their bodies aren't just one big blob of tissue - there are many processes which go on inside us, and we need to consider how toxicants can affect that o The environments are related through the concept of ABSORPTION, which is the extent to which some toxicant from the EXTERNAL environment can enter into our internal environment  What are the different challenges which can present themselves in either environment, and what are the defense systems which our body has for each challenge? o Physical challenge: like getting hit by a bus -- they are hazards that we can see (usually), although some are invisible such as radiation  So our defense is things like avoidance, adrenaline, etc…which on a biological level means neuroendocrine defenses, i.e. epinephrine, cortisol, etc. o Microbial challenges: things like HIV, SARS, pandemic avian flu  These are first handled at the external membrane barrier -- skin, etc.  And then inside us we have general/innate and immunity o Chemical challenges: similarly to microbial challenges, there are external barriers in our body for the chemicals we encounter in the environment  Our defense is then external barriers...  i.e. We could breathe something into our lungs and the lungs are the barrier…or even our GI tract  …and then toxicological defenses, which are frequently biochemical in nature (analog of immune system for microbial challenges)  Xenobiotic metabolism is a big issue here, because it studies the way that the body reacts with foreign chemicals which have entered  Speaking of xenobiotic substances, what are some sources of xenobiotic exposure? o Pollution, drugs, plant products Terminology  Define the following terms: endogenous, exogenous, xenobiotic, contaminant, toxicant, anthropogenic. Comment where appropriate. o Endogenous (intrinsic): denotes a substance made within the body  Since the body makes these, they are in GENERAL (but not always) beneficial to the body o Exogenous (extrinsic): denotes a substance entering from outside the body i.e. It comes from the EXTERNAL environment  o Xenobiotic: any exogenous substance not normally found in the body (note that it doesn't mean DANGEROUS!) o Contaminant: any exogenous xenobiotic that is considered undesirable  We have to be careful with this word, because "undesirable" does not mean "toxic" -- it just means undesirable…so beware the difference! o Toxicant: a xenobiotic contaminant that is potentially hazardous to health  So this is a much tighter definition than "contaminant": here we know that it is CERTAINLY bad  One note here is that since a toxicant is a xenobiotic, it is by definition something that is created biologically -- and so when the word "toxicant" or "toxin" is used, it should only refer to biologically created substances o Anthropogenic: any substance produced by human activity (good or bad)  There is a fallacy here: one of the things that many environmental advocates still believe or say is that anthropogenic substances are more hazardous than other types i.e. xenobiotic -- AND THIS IS FALSE  ESPECIALLY BAD when the word "natural" is used and it seems like it is "better" and "not dangerous" -- this just isn't true  There are good, medium, and bad anthropogenic substances just as there are good, medium, and bad xenobiotic ones Flowchart for Toxins  Give a word flow-chart for how a xenobiotic substance gets into our body. For each step, describe the type of analysis which is performed (if applicable). o Xenobiotic in environment -> exposure -> toxicokinetics/pharmacokinetics -> toxicodynamics/pharmacodynamics  Exposure: as discussed before, there are multiple ways in which this can happen  Toxicokinetics: the pathways by which the toxicants are processed, metabolized, distributed, etc.  A SYNONYM for this is pharmacokinetics…although it is more limited to pharmaceutical drugs  Toxicodynamics: what the xenobiotic/metabolic products do to the tissue of the body -- that is, when the xenobiotic/metabolic byproducts react with cell constituents, what changes to physiological function take place? And how does this affect human health?  There is also pharmacodynamics Risk and Exposure  How is "risk" defined? Give an example which demonstrates the nuances of this definition. o Risk is the probability of injury or disease resulting from exposure to a potential hazard o The nuance is that the hazard itself is always seen as POTENTIAL, meaning that a poison that is well secured is POTENTIALLY HAZARDOUS but not RISKY because there is no way we will ever be exposed to it  Talk about how our exposure to some substance is related to risk. o It is very simple: the probable level of health risk is dependent on the degree/likelihood of exposure because as demonstrated above, a substance is not risky if there is NO chance we will ever bump into it  A non-zero level of exposure is relevant when we CONTROL substances instead of banning them (often done when they are useful) o A complex issue related to the exposure-risk relationship is the notion of "no exposure" -- does it mean no risk?  In a way it does, but since a substance can still hang around in the environment after it has been banned (especially if it is persistent), it is very difficult to fully arrive at a "no exposure" state  Thus we have the concept of virtual elimination: the idea that we can try our best to bans something…we try to get rid of them…but of course there will always be a little bit left  What are some sources of exposure to chemicals? Briefly discuss each. o Environmental: air, water, food o Occupational: hazards in the work place o Therapeutic: things like drugs, medical device o Diet: what is in our foods  Note that therapeutic and dietary sources are getting increasingly mixed up because there are lots of natural medications going on (i.e. herbal products) these days  i.e. Nutraceuticals are also part of food now -- they are food in nature but they have pharmaceutical properties  i.e. Soy milk: high in certain types of hormone-like substances…so people think that by taking soy milk, they will maintain their hormone levels and avoid menopausal symptoms o Accidental: like if you have a large storage facility full of chemicals…and they are accidentally released o Deliberate: think Yushchenko…or also suicidal poisoning  Explain what the concept of toxicity is. o Toxicity is a function of the effectiDOSE (how much) of a xenobiotic AT its target site, integrated over TIME (how long).  As we see in the next question, the EFFECTIVE DOSE may not always be the same as the amount of the thing which we take in  What is the concept of internal exposure/dose? o The idea is that when we absorb a xenobiotic into our bloodstream, that thing is transformed by toxicokinetic processes such that the internal dose is quite different than the external dose  It is the cell or tissue that experiences the internal dose and so the ID is actually the thing which is most directly relevant to our health  Define route of exposure, give examples, and explain why we care. o The route of exposure is essentially the SITE at which the toxin enters the body o We care about this because:  It is an important determinant of the ultimate dose -- that is, the amount/rate of absorption from the external into the internal environment is affected by the ROUTE through which it enters  Also, in the case of a local toxic effect, the place where it enters will be the place where the effect is seen  Note however that there are also SYSTEMIC responses, where the effects are felt all over the body and not just locally  Also it is notably that usually a given toxicant has a characteristic route of exposure -- i.e. some drug gets into us the same way every time  However, sometimes toxicants can enter in more than one way -- i.e. something in water could be drank by us but we could also absorb it dermally through the shower o The sites/routes of exposure can include:  Dermal (skin) -- although the skin is a barrier at times, it is also QUITE thin and many substances can pass through the skin to varying extents…get through the bloodstream and contaminate our bodies…  Inhalation (lung) -- breathing/inhaling…usually gas/vapor but also a dust contaminant  Oral (GI) -- ultimately the small intestine in the GI tract  Injection -- right into the bloodstream baby Dose, Time, etc.  What are the two time-related aspects of exposure which ultimately affect DOSE? o The concept of DURATION: how long an organism is exposed to a chemical for o But also, FREQUENCY: whether we are exposed in a continuous manner…or if it is more episodic (and of course, how often the episodes are, etc.)  Also explain a time-related characteristic that has to do with a given substance's NATURE (as opposed to dose). o Here the idea we are referring to is acute exposure vs. chronic exposure o Acute exposure is a single and time-limited exposure  As a related