PPCPs Human Toxicology

1. PPCPs Human Toxicology Mark Maddaloni Dr. P.H., DABT USEPA – Region 2 October 26, 2005

2. Introduction Overview of PPCPs Pharmaceuticals are chemicals that possess selective pharmacological actions  when administered within a prescribed dose range, they have a specified beneficial effect along with assorted side effects  on the positive side, as a group they meet a “safe and effective” threshold established by the FDA  Personal Care Products constitute a wide array of products

3. Toxicology Assessment (overview) • Pharmaceuticals undergo extensive laboratory testing and clinical trials before receiving FDA approval • Cosmetics – no statutory provision for pre-market safety testing  no product may be marketed if it contains “a poisonous or deleterious substance which may render it injurious to health (FD&C Act 601a)  EU takes a more “precautionary” approach • Other PCPs

4. Article on PCPs Reported in British Press – The Independent • How toxic is your bathroom? • Be warned: your daily beauty regime could be taking years off your life. Pat Thomas reports on the chemical timebomb in your cosmetics cabinet • Published: 24 October 2005 • Earlier this year, the US Food and Drug Administration (FDA) did something amazing. It issued an unprecedented warning to the cosmetics industry that it was time to inform consumers that most personal care products have not been safety tested.

5. Common PCPs of concern • Synthetic musks • Immunologic effects in mussels • Parabens • Used as preservatives in foods, drugs, cosmetics • Possible estrogenic effects • Sunscreen agents • PABA derivatives, cinnamates, benzophenones • Skin lesions in animal models, photo carcinogenicity? • Phthalates • Widespread additive - found in perfumes, hair sprays • Reproductive concern • Alkylphenol ethoxylate surfactants • Cleansing agents • Possible estrogenic effects

6. Personal Care Products as Exposure Sources for Conventional Pollutants • Ayurveda and folk remedies (e.g., litargirio, or litharge): lead (Pb) and other metals (upwards of 80% by weight), mercury in skin lightening creams • Ritualistic Hg use – NYCDEP investigating Hg spikes in wastewater treatment plants • Dermal products: phthalates (esp. diethyl and dibutyl), solvents, dyes, parabens (4-hydroxybenzoic acid alkyl esters) • Lice and tick control shampoos: lindane and permethrins • Shampoos and soaps: alkylphenolic surfactants

7. Drug Development

8. Pre-Clinical Toxicity Testing for Pharmaceuticals • In vitro genotoxicity • Pharmacologic profile • Metabolic studies (ADME) • Acute toxicity testing in two species • Therapeutic Index (TI) = LD50ED50 • Sub-chronic studies (2 weeks – 3 months) • Chronic studies

9. Toxicology Assessment (con’d) • Pharmaceuticals • Limited clinical trials (require IRB approval) • NDA – FDA approval • Post-marketing clinical monitoring and case reports (e.g., MMWR) of serious side effects associated with therapeutic use (e.g., Vioxx) • No equivalent toxicity evaluations for PCPs

10. Low-Dose Toxicity Assessment • Non-carcinogens - Approach employed by EPA to establish daily exposure levels “likely to be without an appreciable risk of deleterious effects over a lifetime” (RAGS, 1989)  RfD • Carcinogens - EPA Cancer Guidelines (less applicable, but may pertain to some antineoplastic and hormonal replacement agents)

11. RfD Development • Literature review • Identification of a critical study • The RfD is developed from a NOAEL for the most sensitive toxic endpoint based in part on the assumption that if the most sensitive toxic effect is prevented, all toxic effects are prevented

12. Default Assumption Using Uncertainty Factors M. Dourson Meek et al., 1994; IPCS, 1994, 2001; Rademaker and Linders, 1994; Pohl and Abdin, 1995; EPA multiple references 11

13. DrinkingWater Health Advisory • The Lifetime HA is considered protective of lifetime exposures and is usually based on chronic or subchronic or other more relevant experimental data. The Lifetime HA is based on the chronic oral RfD, adjusted for a 70 kg adult drinking 2 L water per day; the value is apportioned by a relative source contribution, e.g., 20%.

14. Issues of Toxicological Significance Ecological (Antibiotics and hormones in wastewater are recognized for potentially far reaching implications on ecosystems) Human Health • Hormesis • Sensitive subpopulations • Mixtures

15. Hormesis Hormesis - low-dose stimulation, high-dose inhibition

16. Hormesis • Underlying MOA not well characterized • Low-level stimulation may not be beneficial • Potential confounding factors • Extrapolation to populations (see graph) • Concurrent exposure to similarly acting agents

17. Sensitive Subpopulations • Hypersensitivity Reactions • Induction/elicitation (e.g., PCN) • Infants • Higher exposure per kg body wgt • Less metabolic capacity (silver lining  apap) • Developing nervous system, BBB • Pregnancy • Sensitivity to reproductive toxins (e.g., Accutane)

18. CONTRAINDICATIONS AND WARNINGS Accutane must not be used by female patients who are or may become pregnant. There is an extremely high risk that severe birth defects will result if pregnancy occurs while taking Accutane in any amount, even for short periods of time. Potentially any fetus exposed during pregnancy can be affected. There are no accurate means of determining whether an exposed fetus has been affected.

19. Mixtures (One of the last frontiers of toxicology) • Types of Interactions • Antagonism • Additivity EPA risk assessment methodology HQ = CDI/RfD HI = sum of HQs for chemicals with similar MOA/endpoint • Synergism (used in pharmaceuticals) • e.g. antibiotic combinations  sequential blocks

20. Chemical Mixtures (Example of Additivity) Tentatively Identified Compounds at Hobart: Metaxalone Codeine Hydrocodeine Methadone Hydrocodeine Dihydrocodeine Demerol Butalbital