CHEM3700 Environmental Chemistry Lab Prof. John Shim

Environmental Toxicology: A chemistry perspective

Dr. Ann Richard National Center for Computational Toxicology Office of Research & Development US Environmental Protection Agency Research Triangle Park, NC [email protected]

This work was reviewed by EPA and approved for publication but does not necessarily reflect official Agency policy. What do we mean by chemical toxicity? Some questions?

 Are chemicals inherently good or bad?

 Which are less toxic –man‐ made (synthetic) or natural chemicals?

 What do we mean by “poisons” or “toxic”?

 How does toxicity differ from hazard and risk? Define chemical toxicity

 Chemical causes adverse effects in humans or animals  e.g., irritation, birth defects, sickness, cancer, death!  Can depend on:  Dose (how much of the chemical?)  Time of dosing (acute vs chronic, pregnancy trimester)  Species (humans, primates, dogs, rats, mice, bees)  Sex (male vs female)  Age (old vs young)  Route of exposure (e.g., inhalation, oral, IP) Are chemicals good or bad?  Drugs?

 Pesticides?

 Vitamins?

 Preservatives? I guess it all depends.  Solvents?

 Plasticizers? Depends on what?

 On and on… Are chemicals good or bad?  Drugs?  Depends on what the chemical is used for.  Pesticides?  Depends on how inherently  Vitamins? toxic the chemical is and how much is used (with appropriate cautions).  Preservatives?  Depends on whether people  Solvents? are intentionally or unintentionally exposed (e.g.,  Plasticizers? food).  Depends on the risk/benefits  On and on…  And on and on… Facts: Man‐made vs. Natural chemicals

 There are many more natural chemicals than man- made chemicals occurring in the environment  The most toxic chemicals known are naturally occurring (e.g., botulin, aflatoxin)  Life has evolved alongside naturally occurring chemicals  Many foods contain toxins in small amounts Cyanide Phytohaemagglutinin

Bromelain

Botulinum Solanine Aflatoxin What’s the deal with man‐made chemicals?

 Unintentional or involuntary exposures  Persistence and accumulation in the environment (or our bodies)  Doses to which we are exposed can exceed safe levels  Occupational workers  Superfund sites  Lead in homes  Chemicals in drinking water  Cumulative pesticide levels in food  Chemicals leaching from food packaging  And on and on… Define chemical toxicity

 Chemical causes adverse effects in humans or animals  e.g., irritation, birth defects, sickness, cancer, death!  Can depend on:  Dose (how much of the chemical?)  Time of dosing (acute vs chronic, pregnancy trimester)  Species (humans, primates, dogs, rats, mice, bees)  Sex (male vs female)  Age (old vs young)  Route of exposure (e.g., inhalation, oral, IP) How do we determine toxicity of chemicals? If the chemical is available and of sufficient concern:  Animal studies (expensive, controversial, time-consuming)  In vitro (in a petri dish, test tube or plates) studies measuring bioactivity at enzyme targets or in cells

If the chemical is new or not available:  Expert judgement, weight-of-evidence (partial data)  Structure-activity relationships, i.e. does the chemical “look like” a chemical whose toxicity is known

Regulations:  Drugs, pesticides  Food additives, industrial chemicals, personal care products, etc. Structure‐Activity Relationships (SAR):

Activity = f (Structure)

H3C

active inactive

Methyl group leads to loss of carcinogenic activity SAR: Generalization

Statistical association Mechanistic hypothesis

active

H3C Class PAHs activating feature bay region inactive modulating feature steric hindrance Toxicity can be exquisitely sensitive to structure, e.g. Thalidomide Teratogen Sedative (causes serious birth defects in humans) Building Structure‐activity relationships

Toxicity data Toxicity Monographs Data Sources, references

Structure search; Analogue search; Fragment search SAR Expert judgment Chemical Metabolism Properties Structures, Mechanisms Reaction chemistry Properties Models Prior SAR models Models Structural Alerts Lab assignment: Research an environmental chemical using public on‐line tools

 Each student is assigned a chemical name & InChI (structure)  Use EPA’s Chemical Dashboard & ChemSpider to find:  Chemical structure  Chemical IDs (synonyms, CAS)  Properties (e.g., mass, persistence)  Main use(s) of chemical, how do people get exposed?  Toxicity?  Research topics?  Potential for being an “endocrine disruptor” as inferred by binding to the Estrogen receptor  Any interesting facts that you didn’t know and want to share with the class! EPA’s Chemistry Dashboard https://comptox.epa.gov/dashboard EPA’s Chemistry Dashboard https://comptox.epa.gov/dashboard ChemSpider https://comptox.epa.gov/dashboard Lab assignment: Research an environmental chemical using public on‐line tools

 Find classmate with same chemical number in front of name on card  Pool search results and help each other fill in missing data  Determine the “chemical class” to which both chemicals belong  What general properties belong to the class?  Report main findings of interest to group