PPCPs Human Toxicology

Mark Maddaloni Dr. P.H., DABTMark Maddaloni Dr. P.H., DABT

USEPA – Region 2USEPA – Region 2

October 26, 2005October 26, 2005

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

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

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.

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

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

Drug Development

Pre-Clinical Toxicity Testing for Pharmaceuticals

In vitro genotoxicity Pharmacologic profile Metabolic studies (ADME) Acute toxicity testing in two species

Therapeutic Index (TI) = LD50ED50

Sub-chronic studies (2 weeks – 3 months) Chronic studies

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

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)

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

M. DoursonDefault Assumption Using Uncertainty FactorsDefault Assumption Using Uncertainty Factors

Ufs HealthCanada

IPCS RIVM ATSDR EPA

Interhuman 10(3.16 x 3.16)

10(3.16 x 3.16)

10 10 10

Animal toHuman

10(2.5 x 4.0)

10(2.5 x 4.0)

10 10 10

Subchronicto chronic

10 NA 10

LOAEL toNOAEL

10 10 10

Incompletedatabase

1-100 1-100

NA NA 10

ModifyingFactor

1-10 1-10 NA NA NA

Meek et al., 1994; IPCS, 1994, 2001; Rademaker and Linders, 1994; Pohl and Abdin, 1995; EPA multiple references

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Drinking Water 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%.

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

Hormesis

Hormesis - low-dose stimulation, high-dose inhibition

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

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)

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.

Mixtures (One of the last frontiers of toxicology)

Types of Interactions Antagonism

AdditivityEPA 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

Chemical Mixtures (Example of Additivity)

Tentatively Identified Compounds at Hobart:Metaxalone

CodeineHydrocodeine

MethadoneHydrocodeine

DihydrocodeineDemerolButalbital