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Principles of : The Study of

Arizona Water Issues The University of Arizona – HWR 203 1 Adopted from: Casarez/ Donnelly The study of the adverse effects of a toxicant on living organisms • Adverse effects – any change from an organism’s normal state – dependent upon the concentration of active compound at the target site for a sufficient time. • Toxicant () – any agent capable of producing a deleterious response in a biological system

Arizona Water Issues The University of Arizona – HWR 203 2 Adopted from: Casarez/ Donnelly Axioms of Toxicology

• There is a dosage or exposure level that has no observable effect on the health of animals – as measured by methods which have a finite sensitivity to measure dysfunction or injury. (NOAEL)  Does this mean it is safe?

• Any substance can provoke a dysfunction or injury at some degree of exposure – the dose makes the poison. Attenuation of injury can often be achieved by dilution. Complications can occur when there is exposure to more than one agent – even at “non-toxic” doses. In general, laboratory studies do not look at these complicated cases.  What does this say about the state of our knowledge?

Arizona Water Issues The University of Arizona – HWR 203 3 Adopted from: Casarez/ Donnelly Axioms of Toxicology

• There is essential uniformity in the biochemistry in similar species – among biological mechanisms in mammals. This means animal data is extrapolated for predictions in humans.  What are advantages/disadvantages of animal testing?

• Toxicological data from animal experiments can be used to assess the degree of exposure or dosage that will NOT adversely affect human health. However, potential or real differences between animals and humans require that judgmental factors be applied when extrapolating animal threshold doses in order to insure an adequate margin of safety for humans.  Animal testing must be extrapolated carefully  We should error on the side of caution

Arizona Water Issues The University of Arizona – HWR 203 4 Adopted from: Casarez/ Donnelly Dose Dose: The amount of chemical entering the body

This is usually given as mg of chemical/kg of body weight = mg/kg

The dose is dependent upon: * The environmental concentration * The properties of the toxicant *The frequency of exposure *The length of exposure * The exposure pathway (route)

Arizona Water Issues The University of Arizona – HWR 203 5 Adopted from: Casarez/ Donnelly What is a Response?

The degree and spectra of responses depend upon the dose and the organism • Change from normal state – could be on the molecular, cellular, organ, or organism level--the symptoms • Local vs. Systemic • Reversible vs. Irreversible • Immediate vs. Delayed • Graded or Quantal – continually varying vs. all-or-none

Arizona Water Issues The University of Arizona – HWR 203 6 Adopted from: Casarez/ Donnelly Dose-Response Relationship:

 As the dose of a toxicant increases, so does the response

4

Limitations • Often derived from acute exposure data. • Species variation 3 RESPONSE

Ranges: 4 Maximum Response 2 2-3 Linear Range 0-1 NOAEL 0 1 DOSE Dose determines the biological response Arizona Water Issues The University of Arizona – HWR 203 7 Adopted from: Casarez/ Donnelly LD50

• If Mortality is the 100% response, the dose that is lethal to 50% of the

population LD50 can be generated from this 50% curve Not everybody reacts in the same way to a toxic exposure LD (or ED) 50 Dose 10-30 fold variation w/in a population!

Arizona Water Issues The University of Arizona – HWR 203 8 Adopted from: Casarez/ Donnelly LD50 Comparison

Chemical LD50 (mg/kg) Ethyl 10,000 Sodium Chloride 4,000 Ferrous Sulfate 1,500 Morphine Sulfate 900 Strychnine Sulfate 150 Nicotine 1 (1 mg) Black Widow 0.55 Curare 0.50 Rattle Snake 0.24 Dioxin (TCDD) 0.001 Botulinum 0.0001

Different toxicants can be compared--lowest dose is most potent

Arizona Water Issues The University of Arizona – HWR 203 9 Adopted from: Casarez/ Donnelly Sources of Caffeine

Source Amount Dose if 150lbs mg / 12 oz ie. 68 kg Coffee - brew 137-260 250/16oz or 3.6 mg/kg Coffee - decaf 5 Iced tea 70 Nestea 25 Coke 34 102/36oz or 1.5 mg/kg Mt. Dew 55 Monster, RedBull 80-160 240/24oz or 3.5 mg/kg

Source: www.energyfiend.com/the-caffeine-database

Arizona Water Issues The University of Arizona – HWR 203 10 Adopted from: Casarez/ Donnelly Read Carefully!

“The actual caffeine content for many energy drinks is not easily identified on product packaging or via the Internet. The total amount of caffeine contained in some cans or bottles of energy drinks can exceed 500 mg (equivalent to 14 cans of common caffeinated soft drinks) and is clearly high enough to result in caffeine .23 A of caffeine is considered to be 200 to 400 mg/kg.24” Clinical Report–Sports Drinks and Energy Drinks for Children and Adolescents: Are They Appropriate? Guidance for the Clinician in Rendering Pediatric Care: www.pediatrics.org/cgi/doi/10.1542/peds.2011-0965 WARNING: distinguish amount from dose

Arizona Water Issues The University of Arizona – HWR 203 11 Adopted from: Casarez/ Donnelly Toxicity vs. Health Impacts

“MY COUSIN IS 16 YEARS OLD AND HE WOULD DRINK UP TO FIVE MONSTERS A DAY. FOR THE PAST MONTH HES BEEN ACTING REALLY WEIRD. HE TALKS TO HIMSELF, HES REALLY SHAKY, HE CANT SIT NOT EVEN FOR A MINUTE. HE HAS TO BE MOVING AND HE SLEEPS ALOT THE FAMILY IS SO WORRIED. ITS SCARY TO SEE WHAT A ENERGY DRINK IS DOING TO MY TEENAGE COUSIN.” Anonymous www.aboutlawsuits.com/energy-drink-health-risk-warnings-1161/

Arizona Water Issues The University of Arizona – HWR 203 12 Adopted from: Casarez/ Donnelly Exposure Routes & Doses

Chemical Animal Route LD50 Dose Caffeine Mouse Oral 620 mg/kg Rat Oral 192 mg/kg Rat IV 105 mg/kg Mouse IV 68 mg/kg Amt: 200 g rat  38 mg; 70 kg person  13,440 mg = 54 cups HgCl (II) Rat Oral 37 mg/kg Mouse Oral 10 mg/kg Dimethylarsenic Rat Oral 700 mg/kg (cotton defoilant)

Arizona Water Issues The University of Arizona – HWR 203 13 Adopted from: Casarez/ Donnelly Factors Influencing Toxicity

• Related to the: – chemical –person – exposure – environment

Arizona Water Issues The University of Arizona – HWR 203 14 Adopted from: Casarez/ Donnelly The Human Factors

• Gender •Age • Duration • Route of exposure • Genetics • Species variation

Arizona Water Issues The University of Arizona – HWR 203 15 Adopted from: Casarez/ Donnelly Individual Susceptibility There can be 10-30 fold difference in response to a toxicant in a population

• Genetics-species, strain variation, interindividual variations (yet still can extrapolate between mammals--similar biological mechanisms) • Gender (gasoline nephrotox in male mice only) • Age--young (old too) – underdeveloped excretory mechanisms – underdeveloped biotransformation enzymes – underdeveloped blood-brain barrier

Arizona Water Issues The University of Arizona – HWR 203 16 Adopted from: Casarez/ Donnelly Individual Susceptibility

• Age--old – changes in excretion and metabolism rates, body fat • Nutritional status • Health conditions • Previous or Concurrent Exposures – additive --antagonistic – Synergistic  The disadvantaged are often more susceptible

Arizona Water Issues The University of Arizona – HWR 203 17 Adopted from: Casarez/ Donnelly Exposure: Duration

Acute < 24hr usually 1 exposure Subacute 1 month repeated doses Subchronic 1-3mo repeated doses Chronic > 3mo repeated doses

Over time, the amount of chemical in the body can build up, it can redistribute, or it can overwhelm repair and removal mechanisms

Arizona Water Issues The University of Arizona – HWR 203 18 Adopted from: Casarez/ Donnelly Exposure: Pathways

• Routes and Sites of Exposure – Injection • intravenous – Inhalation (Lungs) – Injection • Intraperitoneal, intramuscular – Ingestion (Gastrointestinal Tract) – Dermal/Topical (Skin)

• Typical Effectiveness of Route of Exposure iv > inhale > ip > im > ingest > topical

Arizona Water Issues The University of Arizona – HWR 203 19 Adopted from: Casarez/ Donnelly Response to Toxic Substances

• Skin/eyes • Central Nervous system • Respiratory tract • Circulation system • Liver / Kidneys • Digestive system • Reproductive system • Bones and joints • Cancer and others

Arizona Water Issues The University of Arizona – HWR 203 20 Adopted from: Casarez/ Donnelly Target Organs: adverse effect is dependent upon the concentration of active compound at the target site for enough time • Not all organs are affected equally – greater susceptibility of the target organ – higher concentration of active compound • Liver--high blood flow, oxidative reactions • Kidney--high blood flow, concentrates chemicals • Lung--high blood flow, site of exposure • Neurons--oxygen dependent, irreversible damage • Myocardium--oxygen dependent • Bone marrow, intestinal mucosa--rapid divide

Arizona Water Issues The University of Arizona – HWR 203 21 Adopted from: Casarez/ Donnelly ADME: Absorption, Distribution, Metabolism, and Excretion

• Once a living organism has been exposed to a toxicant, the compound must get into the body and to its target site in an active form in order to cause an adverse effect. • The body has defenses: – Membrane barriers • passive and facilitated diffusion, active transport – Biotransformation enzymes, antioxidants – Elimination mechanisms

Arizona Water Issues The University of Arizona – HWR 203 22 Adopted from: Casarez/ Donnelly Absorption: ability of a chemical to enter the blood • Inhalation--readily absorb gases into the blood stream via the alveoli. (Large alveolar surface, high blood flow, and proximity of blood to alveolar air) • Ingestion--absorption through GI tract stomach (acids), small intestine (long contact time, large surface area--villi; bases and transporters for others) • Dermal--absorption through epidermis (stratum corneum), then dermis; site and condition of skin

Arizona Water Issues The University of Arizona – HWR 203 23 Adopted from: Casarez/ Donnelly Distribution: the process in which a chemical agent translocates throughout the body

• Blood carries the agent to and from its site of action, storage depots, organs of transformation, and organs of elimination • Rate of distribution (rapid) dependent upon – blood flow – characteristics of toxicant (affinity for the tissue, and the partition coefficient) • Distribution may change over time

Arizona Water Issues The University of Arizona – HWR 203 24 Adopted from: Casarez/ Donnelly Distribution: Storage and Binding • Storage in Adipose tissue--Very lipophylic compounds (DDT) will store in fat. Rapid mobilization of the fat (starvation) can rapidly increase blood concentration • Storage in Bone--Chemicals analogous to Calcium--Fluoride, Lead, Strontium • Binding to Plasma proteins--can displace endogenous compounds. Only free is available for adverse effects or excretion

Arizona Water Issues The University of Arizona – HWR 203 25 Adopted from: Casarez/ Donnelly Complex Mixtures

• smoke • Breakdown products of PCE • Gasoline

• Potential Health Effects: – May be similar to “dominant” chemical – potential interactions VERY uncertain

 Exposure guidelines are just now being written

Arizona Water Issues The University of Arizona – HWR 203 26 Adopted from: Casarez/ Donnelly Oral Reference Dose (RfD)

• An estimate, with uncertainty spanning perhaps an order of magnitude, of a daily oral exposure to the human population (including sensitive subgroups) that is likely to be without an appreciable risk of deleterious effects during a lifetime.

RfD = NOAEL/(uncertainty factors>100) Units: mg/kg/day

Arizona Water Issues The University of Arizona – HWR 203 27 Adopted from: Casarez/ Donnelly Complex Example

Concentration (mg/L) / Oral Ref Dose (mg/kg*d) = Non carcinogenic Risk factor (Rn)

Concentration (mg/L) * Slope Factor (kg*d/mg) = Carcinogenic Risk factor (Rc)

Rn + Rc = Rtotal (compound specific) Volume Weighted Average Concentrations from Both Wells total total Percent R Rank Cumulative Percent Risk Chemical Water Concentration (mg/L) Water Quality Standard (mg/L) Oral RfD (mg/kg*d) Oral SF (kg*d/mg) R oral,noncarcinogenic score) (chemical R oral, carcinogenic score) (chemical R Arsenic 0.055 0.010 3.0E-04 1.5 183 0.083 183 56.7 1 56.7 Fluoride 7.7 4/2 0.06 128 128 39.7 2 96.4 Nitrate 17 10 1.6 10.6 11 3.3 3 99.7 Barium 0.060 2 0.07 0.86 1 0.3 4 100 323 Arizona Water Issues The University of Arizona – HWR 203 28 Adopted from: Casarez/ Donnelly Target Sites: Mechanisms of Action

• Adverse effects can occur at the level of the molecule, cell, organ, or organism • Molecularly, chemical can interact with Proteins Lipids DNA • Cellularly, chemical can – interfere with receptor-ligand binding – interfere with membrane function – interfere with cellular energy production – bind to biomolecules – perturb homeostasis (Ca)

Arizona Water Issues The University of Arizona – HWR 203 29 Adopted from: Casarez/ Donnelly Excretion: Toxicants are eliminated from the body by several routes

• Urinary excretion – water soluble products are filtered out of the blood by the kidney and excreted into the urine • Exhalation – Volatile compounds are exhaled by breathing • Biliary Excretion via Fecal Excretion – Compounds can be extracted by the liver and excreted into the bile. The bile drains into the small intestine and is eliminated in the feces. • Milk Sweat Saliva

Arizona Water Issues The University of Arizona – HWR 203 30 Adopted from: Casarez/ Donnelly Metabolism: adverse effect depends on the concentration of active compound at the target site over time • The process by which the administered chemical (parent compounds) are modified by the organism by enzymatic reactions. •1o objective--make chemical agents more water soluble and easier to excrete – decr. lipid solubility --> decr. amount at target – increase excretion rate --> decrease toxicity • Bioactivation--Biotransformation can result in the formation of reactive metabolites

Arizona Water Issues The University of Arizona – HWR 203 31 Adopted from: Casarez/ Donnelly Biotransformation (Metabolism)

• Can drastically effect the rate of clearance of Compound Without With compounds Metabolism Metabolism Ethanol 4 weeks 10mL/hr • Can occur at any point during the Phenobarbital 5 months 8hrs compound’s journey from DDT infinity Days to weeks absorption to excretion

Arizona Water Issues The University of Arizona – HWR 203 3 Adopted from: Casarez/ Donnelly 2 Biotransformation

• Key organs in biotransformation – LIVER (high) – Lung, Kidney, Intestine (medium) –Others (low) • Biotransformation Pathways * Phase I--make the toxicant more water soluble * Phase II--Links with a soluble endogenous agent (conjugation)

Arizona Water Issues The University of Arizona – HWR 203 33 Adopted from: Casarez/ Donnelly Toxicology • Exposure + Hazard = Risk • All substances can be a poison • Dose determines the response • Pathway, Duration of Frequency of Exposure and Chemical determine Dose • Absorption, Distribution, Metabolism & Excretion • The extent of the effect is dependent upon the concentration of the active compound at its site of action over time • Bioactivation: compounds to reactive metabolites • Individual variation of the organism will affect ADME

Arizona Water Issues The University of Arizona – HWR 203 34 Adopted from: Casarez/ Donnelly EPA Risk Paradigm

Health Chemical Effect

Emission Transport Receptor

Arizona Water Issues The University of Arizona – HWR 203 35 Adopted from: Casarez/ Donnelly Conclusions

 Due to the variability of humans, it is extremely difficult to establish causation with any degree of certainty  Prevention is the most effective method to minimize the impact of exposure to environmental chemicals  Human exposures are most often associated with complex mixtures.  All populations include sensitive and resistant individuals, thus it is difficult to predict effects based on an “average”.  Uncertainty is a fact of life

Arizona Water Issues The University of Arizona – HWR 203 36 Adopted from: Casarez/ Donnelly What is a Poison?

All substances are poisons; there is none that is not a poison. The right dose differentiates a poison and a remedy.

Paracelsus (1493-1541)

Arizona Water Issues The University of Arizona – HWR 203 37 Adopted from: Casarez/ Donnelly