Toxicology Made Simple February 7, 2006

1. Toxicology Made SimpleFebruary 7, 2006 Mary McDaniel, D.O., J.D., M.P.H. McDaniel Lambert Inc. mfmcdaniel@mclam.com

2. Paracelsus “The dose alone makes the poison.”

4. Toxicity vs. Hazard • Toxicity is the inherent potential for a substance to cause harm. It is only one factor in determining whether a hazard exists. • Hazard is the practical likelihood that the chemical will cause harm and that depends on exposure, susceptibility, and sensitivity.

5. Dose-Response Relationship • The key to understanding the toxicity of any chemical is its dose-response relationship. This means, how does the body respond when exposed to progressively higher doses of chemical.

6. The LD50 (Lethal Dose 50) • This test examines the relationship between dose and the most extreme response—death. • The dose causing death in half (50%) of the animals exposed is called the LD50. • The more potent or toxic the chemical, the lower the LD50 and the smaller the dose needed to cause death.

7. The LD50 LD50 Dose-Response Results for Methyl-Ethyl-Deathyl-Meatloaf

8. How Much Is Too Much? • The LD50 is frequently used to rank the toxicity of chemicals.

9. Toxicity Terms • LD50 (Lethal Dose, 50% kill) – the dose of material that is ingested, injected or applied to the skin that kills 50% of the treated population. Often expressed as mg chemical/kg body weight. • LC50 (Lethal Concentration, 50% kill) – refers to the concentration of inhaled material that kills 50% of the treated population. Expressed as either parts per million (ppm) or mg/m3 of inhaled material.

10. Dose Levels • The dose level at which the response (in this case, death) begins is called the threshold level. • Toxicologist also investigate dose-relationships for other symptoms of toxicity such as: • Irritation • Anemia • Liver enzyme changes • In those studies, the threshold level is the no observed adverse effect level – NOAEL. • The no observed effect - NOEL

11. Dose-Response Relationship for a Typical Chemical

12. One Size Doesn’t Fit All • The dose-response curve in the graph is S-shaped since each individual responds a little differently to the same dose • This difference in susceptibility is called biologic variability.

13. What’s Your Limit? • Occupational exposure limits are set to protect healthy workers and do not take into consideration the unique susceptibilities of the very young, very old, the immuno suppressed or other sensitive individuals.

14. Is Sugar That Bad?

15. What About TCE?

16. How are workers exposed? • Inhalation • Airborne chemicals entering the lung may act directly, causing minor irritation or even pulmonary edema. • Airborne chemicals may also be absorbed into the bloodstream. • Skin and Eye • The eyes are not a major route of exposure. But are especially susceptible to direct acting chemicals that irritate or destroy tissue.

17. How are workers exposed cont’d • Ingestion • Primarily instances where food, coffee or cigarette has become contaminated • Occurs indirectly after first being inhaled incidentally • Injection • The least likely route of exposure. • Usually contact with used syringes • Risk is primarily blood-borne pathogens causing illnesses ( Hepatitis B, AIDS)

18. Injuries can be local or long distant • Some chemicals may cause injury at the point of initial contact - eyes, skin, respiratory and digestive tract. (corrosives) • Other chemicals cause systemic toxicity after passing through certain barriers, e.g. the skin, and require absorption and distribution to the nervous and reproductive system and the fetus. (solvents)

19. Acute and Chronic Exposure/Health Effects • Acute Exposure • A single exposure to a chemical • If resolved on its own—acute health effect • If it persists for months or years—chronic health effect • Chronic Exposure • Usually lower dose exposure for long periods of time associated with chronic effects.

20. What Is Hazardous? • Anything with an exposure limit by • ACGIH TLV - Threshold Limit Value • OSHA PEL - Permissible Exposure Limit • Anything listed as a carcinogen by • NTP - National Toxicology Program • IARC - International Agency for Research on Cancer • OSHA

21. Definition of Hazardous cont.... • Physical hazards such as flammable, explosive, oxidizer, pyrophoric, water-reactive • Health hazards such as irritation, corrosive, toxic, sensitizer, target organ, developmental or reproductive toxicant, carcinogen (even if not on one of the lists)

22. Health Hazard Definitions cont.... • (Severe) Skin Irritant - primary skin irritation score is 5 or more or human evidence suggests irritation. May be considered severe irritant as indicated in ANSI Labeling Standard • Skin Irritant - per ANSI Labeling Standard, primary skin irritation score between 3 and 5 or human evidence

23. Agency Definitions of Corrosivity Vary • EPA: PH less than or equal to 2 or greater than or equal to 12.5 • Consumer Product Safety Commission (CPSC): The structure of the skin at site of contact is destroyed or irreversibly changed in 24 hours or less. • Department of Transportation (DOT): The structure of the skin at site of contact is destroyed or irreversibly changed in 4 hours or less. • OSHA: Visible destruction or irreversible alteration in living tissue at the site of contact.

24. Health Hazard Definitions cont.... • Chronic Toxicity (target organs, cancer, mutagenicity, developmental and reproductive toxicants) - weight of evidence approach, one well conducted study of adverse effects requires warning on the MSDS

25. Health Hazard Definitions cont.... • Allergens (Sensitizers) • Sensitizers are chemicals that cause an allergic response. • Nickel, • Photosensitizers require exposure to sunlight—typically while on the skin—to cause allergic response.

26. Health Hazard Definitions cont.... • Asphyxiants interfere with the blood’s ability to oxygenate tissues. • Simple axphyxiants are biologically inert gases that compete with oxygen at high concentrations and result in insufficient amounts of required oxygen. e.g. nitrogen • Chemical axphyxiants, through chemical action, interfere with the body’s ability to use oxygen. • e.g. hydrogen cyanide

27. How Irritating • Eye Irritant - transient changes of the cornea (opacity), iris (hyperemia) or conjunctiva (swelling) • Severe Eye Irritant - significant eye injury such as loss of corneal epithelium, corneal opacity, iritis, conjunctivitis. Reversible within 21 days

28. Neurotoxins • Central Nervous System (CNS) toxins • Anesthetics and narcotics • Convulsants • Peripheral Nervous System (PNS) toxins • lead

29. Blood • Bone Marrow. Agents that suppress its function include: • Benzene • Arsenic • Bromine • Methyl chloride • Ionizing radiation

30. Liver Toxicity • The liver is a common target organ of chemical-induced injury. • The liver processes most foreign chemicals • The primary organ for the biotransformation of chemicals • Examples of acute liver injury include: • Lipid Accumulation • Cholestasis • Necrosis • Hepatitis

31. Kidney Toxicity • Directly Toxic agents include: • Metals (Mercury, lead, cadmium) • Halogenated hydrocarbons (carbon tetrachloride and chloroform) • Certain therapeutic agents (phenacetin, aspirin, and certain antibiotics) • Indirect Toxicity: • Depositing crystals in the tubular element of the nephron • Hemolytic agents

32. Pulmonary Toxins • Irritants • Fibrosis • Allergic Reactions • Emphysema • Lung Cancer

33. Reproductive and Developmental Toxicity • Reproductive System • Chemicals impair the ability of males or females to contribute to conception • Developmental Toxins • Interfere with the normal development of a fetus.

34. Chemicals in the news: Chromium • Chromium compounds are widely used in industry • Valence state dramatically affects toxicity and chemical properties

35. Chromium: deadly carcinogen or necessary element? • Both • Chromium III is necessary to maintain blood glucose levels • Chromium VI is classified as a known human carcinogen Stay tuned: more on chromium next week

36. Chemicals in the News : Dioxins, PCBs & Dibenzofurans • Related groups of chemicals referred to as persistent organic pollutants (POPs) • Even found in remote areas of the world near no industrial sources • Pose a long-term threat to environment • Because these types of chemicals are frequently found together, it is hard to accurately analyze human effects

37. Dioxins, PCBs & Dibenzofurans • Consist of aromatic rings with different degrees of chlorination • Have similar modes of toxicity • Accumulate in fatty tissues DIOXIN PCB DIBENZOFURAN

38. Dioxins • 75 chemically related compounds • 2,3,7,8-TCDD is most toxic • Occur naturally as byproducts from incineration • Other manmade sources including chlorine bleaching at pulp paper mills

39. The Scary History of Dioxin • Herbicide Agent Orange Vietnam war 1961-71 • Chemical plant explosion in Italy 1976 • 1978 Love Canal, NY • 1983 Times Beach, Missouri Seveso, Italy 1976

40. How is the Public Exposed to Dioxin? • Emitted as byproduct into the air • Breathing of fumes/ash from municipal garbage incineration • Eating contaminated fish (esp. downstream from paper mills) FLY ASH

41. How Can Workers Be Exposed • Paper pulp mills • Operating incinerators • Some pesticide operations

42. Dioxin Health Effects • Chloracne • Headaches, dizziness, digestive disorders • Generalized aches and pains • Some possibility it causes soft tissue sarcoma

43. Dioxin Health Effects • Change in blood/urine may indicate liver damage • Glucose metabolism • Changes in hormonal levels • Increases the risk of several types of cancer • World Health Organization classifies TCDD a human carcinogen

44. Dioxins are Extremely Toxic to Some Animals • Cancer • Liver & kidney problems • Fetal death • Birth deformities • Some animals are especially susceptible to dioxin • Hard to draw conclusions about human sensitivity - we may not be as sensitive

45. Polychlorinated biphenyls (PCBs) • Widely used from 1930 - 1976 • Component of hydraulic fluids, lubricants, capacitor fluid, flame resistant materials • High thermal stability • Low water solubility

46. PCBs • Strong resistance to chemical degradation • Accumulates in aquatic environments • Found in nearly all mammals, marine species, fish and birds at some level • Magnifies in high levels through food chain transfer (Ex: Oregon whale levels) • Reproductive system is most sensitive

47. Viktor Yushchenko Dec. 2004 June 2004 Jan. 2005

48. PCB Health Effects • Children born to mothers with a high dietary intake of PCBs could have behavioral and immune system problems

49. PCB Health Effects • In workers at PCB manufacturing plants the most common effects were severe acne and rashes • PCBs cause cancer in laboratory animals exposed for long periods of time • USEPA named PCBs a probable human cancer causing chemical

50. Paracelsus “The dose alone makes the poison.”