TOXICOLOGY AND RISK ASSESSMENT

1. ENVIRONMENTAL RISK ASSESSMENT Session 2A TOXICOLOGY AND RISK ASSESSMENT Mark G. Robson, Ph.D., M.P.H. UMDNJ - School of Public Health

7. “What is it that is not poison? All things are poison and nothing is without poison. It is the dose only that makes a thing not a poison.” Paracelsus Paracelsus was a Swiss physician living in the 1500’s.

11. The Legal Definition of Poison • A chemical that has a lethal dose-LD50 less than or equal to 50 mg of chemical/ kg of body weight • 50 mg/kg is approximately 3/4 tsp. for the average adult, and about 1/8 tsp. for the average 2 year old

12. Hazard • This is often used as a synonym for toxicity. Hazard is a more complex concept, as it includes conditions of use. • A hazard has 2 components: • Inherent ability of the chemical to do harm by virtue of its explosiveness, flammability, corrosiveness, toxicity, etc. • The ease with which contact can be established between the chemical and the object of concern.

13. Strychnine The toxicity of strychnine is great, but in a sealed unbreakable container the hazard is low.

14. Gasoline Gasoline is not that toxic in and of itself. It is harmful because it is extremely flammable. If it is ingested, some of the liquid may become aspirated. When taken into the lungs in liquid form, it can produce chemical pneumonitis. Fatality Rate from Petroleum Distillate Pneumonitis is high. For this reason products with greater than 10% petroleum distillates warn not to induce vomiting is ingested. e.g. In children we see the condition when they have ingested something like furniture polish. Energy Crisis of the 1970’s-we saw adults with the condition from siphoning gas from the tank.

15. Dose Time Relationship or How Much and How Often ACUTE TOXICITY: Refers to the ability of a substance to do systemic damage as a result of a one-time exposure of relatively short duration. CHRONIC TOXICITY: Refers to the harmful systemic effects produced by long-term, low-level exposure to chemicals. Chronic toxicity is a far more complex issue.

16. Lethal Dose (LD50) This is a term to describe acute toxicity. Subscript 50 means that the dose was lethal for 50% of the population who had the administered dose. • LD0 There were no resultant deaths • LD100 The entire population died The units for LD50 are in mg of chemical/kg of body weight. The smaller the LD50, the fewer the mg of chemical/kg of body weight will be required to kill the animal. Conversely, the larger the the LD50, the lower the acute toxicity. We can say that LD50 and acute toxicity are inversely related.

17. Some compounds are acutely toxic, but not chronically toxic in lower doses, and in fact can be essential.

18. Vitamin D • Vitamin D is highly acutely toxic, 10 mg/kg or about 400,000 international units/kg. • The pesticide Parathion is also acutely toxic at 10 mg/kg. • Vitamin D is exempted from the hazardous substances labeling act because it is in food (milk) and a drug (sold as a vitamin.) Otherwise, it would be required to carry a poison label. • Everyone of U.S. requires about 10ug per day (400 IU.)

19. Sodium Fluoride • High Acute Oral Toxicity-35 mg/kg • We take it in chronic low does, 1 or 2 mg daily for good dental health • If we exceed a dose of 3 or 4 mg/day we get mottling of tooth enamel in young people • There has been some opposition to water fluoridation. However, epidemiological studies show that there are no effects from long term use of fluoridated water.

20. Sodium Chloride (Table Salt) • Acutely toxic, but essential in daily small doses. Salt has an oral LD50 of about 3g/kg. • There have been deaths of children reported who were given a box of salt to play with. The lethal dose for a child is about 2 tsp. For adults, table salt is a problem for individuals with heart or kidney disease. • The critical part of salt is the sodium atom. We need about 200 mg of sodium per day. People who live and work in hot environments sweat a great deal and require larger amounts of salt. • Average American diet has 8,000-10,0000 mg/day (well above the required amount.)

21. Acutely Non-Toxic – Chronically Toxic • Metallic Mercury: • A one-time ingestion will not cause illness or death. Used to be an issue with thermometers; child chews the thermometer and swallows the contents, and mom goes wild. Really no problem, will pass through and be eliminated in the feces. • But if ingested everyday, could lead to chronic mercury intoxication.

22. Other Examples • LD of Caffeine is approximately 100 cups of strong coffee • LD of Solanine is approximately in 100 to 400 pounds of potatoes • LD of Oxalic Acid is 10 to 20 pounds of spinach or rhubarb • LD of Ethanol in a fifth of Vodka, Gin, or Scotch • LD of Aspirin is about 100 tablets

23. Route of Exposure Three Major Routes: • Penetration through the Skin (Dermal Entry) • Absorption through the Lungs (Inhalation) • Passage across the walls of the Gastrointestinal Tract (Oral) The route of exposure is the pathway by which the chemical gets into the body.

24. When we combine the dose time and the route factors, we get six kinds of toxicity that can be identified for every chemical. The most common way to contact chemicals is dermally. But the skin is a very effective barrier to chemicals. We have about 20 sq.ft. of skin. The second most common route is via inhalation. Lungs are a poor barrier to chemical. We have about 750 sq.ft. of lung surface.

25. Other Routes of Entry • Intravenously – Into the Vein • Intramuscularly – Into a Muscle • Intradermally – Into the Skin • Subcutaeneously – Under the Skin • Intra peritoneally – Into the Peritoneal Cavity

26. Inhalation • Remember the function of the lungs is to deliver O2 from air to blood and CO2 from blood to air. The lung surface is very delicate and very thin membrane, about one cell thick. • The one cell thick membrane allows easy passage of oxygen and other chemicals form the alveolar space to the blood. (This is why people smoke marijuana instead of eating it.) • In addition to the systemic nature-there are also the issues of interference with function • Asbestos and Silica damage the lung surfaces, causing asbestosis and silicosis. There are other examples from cotton dust, coal dust, sugar cane pulp. Collectively these diseases are called pneumoconiosis.

27. Oral • The oral route is through ingestion – mainly through food that we eat. Chemicals enter the body and are absorbed through the G.I. tract. • The absorption can occur anywhere from the mouth to the rectum. The majority of the absorption takes place in the small intestine. • Nitroglycerine is absorbed through the mucus membranes of the mouth, that is why it is taken and placed under the tongue. • Ethyl alcohol is absorbed rapidly in the stomach as well as the intestine, that is why the effects are seen so quickly. It is also why food in the stomach can delay some of the effects.

28. Infants have a different gastric condition than adults • The infant, up to 9 months, has an alkaline environment • Adults have gastric juices that are acidic • One reason why we are so concerned with nitrates in well water and certain food products for children-the alkaline environment enhances the activity of some microorganisms that reduce nitrates to a toxic form. • Some chemicals are actually absorbed better in the rectum. That is why we administer some drugs via a suppository.

29. In General… • Water soluble chemicals go directly from the small intestine to the liver via the hepatic portal vein. • Fat soluble chemicals bypass the liver by going into the lymphatic system, which empties into the blood stream near the heart.

30. There are only a few chemical that are equally toxic by all three routes of exposure. • e.g. Organophosphate Pesticide Parathion • Highly Acutely toxic when absorbed via dermal, oral, and inhalation. • It inhibits the cholinesterase enzyme regardless of exposure route. The cholinesterase enzymes deactivate choline esters. When the cholinesterase is inhibited, acetylcholine is not deactivated, and there is continued stimulation of the parasympathetic nervous system.

31. Other Factors that Influence the Toxicity of a Chemical Species

32. All Sorts of Differences • Nitrobenzene converts hemoglobin to methemoglobin. • Nitrobenzene more toxic to man, cats, and dogs than monkeys, rats, and rabbits. • Physiological peculiarity-Rats do no vomit (or as Dr. Gallo puts it: “Rats don’t wretch.”) • This was of particular interest in looking at the MTBE data. Also, this is why we formulate certain rodenticides that way that we do, since we know that rats cannot empty their stomach contents. • Dogs (as those of you who own dogs know) do vomit

33. So Why Is This Important: • We base the toxicology and the risk assumptions on using animal models, but which animals? • Man and monkey are fairly similar • Monkeys do respond to methanol the same as man • Monkeys do not respond to nitrobenzene the same as man • The use of animal data to human data dates back to the amendments made in 1958 to the Food Additives Amendments Act which is known to most as the Delaney Amendment. • The food additive is considered a carcinogen if it cause cancer in any animal species at any level of exposure.

34. Age • Age has an influence on toxicity in many models • DDT is not acutely toxic to newborn rats, however, it becomes progressively more toxic as the rats mature. The adult LD50 is 200-300 mg/kg. • The organophosphate parathion is more acutely toxic to newborn rats than adults rats. • The age difference is usually a function of the body systems and the ability to metabolize foreign chemicals-the major player being the liver microsomal enzyme system.

35. Sex • There are obvious physical and physiological differences. • Male rats are 10X more sensitive to liver damage than female rats from chronic oral exposure to DDT. • Sex differences are usually a function of hormone activity. • Castration or hormone administration can limit the differences.

36. NutritionState of HealthIndividual SusceptibilityPresence of Other ChemicalsAdaptation

37. Lethal Dose for Humans

38. For inhalation work, we use a different designation: Lethal Concentration 50 (LC50): • LC50 is determined by exposing several groups of animals, usually rats or mice, each to a different air concentration of the chemical for a one-hour period, then they are observed for a 14-day period.

39. 100 LD50 50 % Mortality 0 100 200 300 400 DOSE (mg/kg)

40. 100 50 LD50 % Mortality LD0 0 DOSE (mg/kg)

41. 100 LD50 50 % Mortality LD0 0 DOSE (mg/kg)

42. Chronic Toxicity was recognized first in occupational illness • Greek Physicians noted that certain trades had poorer health- e.g. mining, metallurgy, pottery. • Hippocrates described severe colic in men who extracted metals-Pb poisoning • Pliny wrote of Hg poisoning in miners from the quicksilver mines of Spain

43. Effect Effect Dose No Effect Maximum Effect Dose 0 Threshold

44. FDA has a 100 Fold Margin of Safety • Margin of Safety: • Humans are by far more sensitive than test animals • Weak in human population (young, old, sick.) • 10 X 10= 100 Margin • If no adverse effect = 100 ppm in diet, then maximum dietary concentration= 1 ppm

45. The Gens: Muta, Terato, and Carcino… • Gen – means birth or origin • Muta – means change • Terata – means monster • Carcino – means crab

46. Mutagenesis • Mutation is considered the initiating event in carcinogenesis • Genetic code – message system DNA Genes Chromosomes • A mutation is a change in the genetic code that results in a change in the message

47. Teratogenesis • Abnormalities in developing organisms during uterine life • Congenital malformations in U.S.: 2 in 100 live births • 20% of all pregnancies do not go to term resulting in spontaneous abortion

48. Diseases in the Mother • Viral diseases – Rubella in first trimester • Hereditary – Abnormalities • Nutrition – Starvation or deficiencies, excesses

49. Natural and Man-Made Radiation: • X-rays are potent mutagens and teratogens • Chemicals- germs cells, developing fetus, placenta development, O2 transfer • Some examples: • Steroid Hormones • Vitamin D • Anti-Cancer Drugs • Thalidomide

50. Carcinogenesis • Chemical Carcinogens • 2 Categories: • Genotoxic – DNA damage direct mutation • Epigenetic – Cellular damage