Transcript Slide 1

PPCPs Human Toxicology
Mark Maddaloni Dr. P.H., DABT
USEPA – Region 2
October 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


Parabens




PABA derivatives, cinnamates,
benzophenones
Skin lesions in animal models,
photo carcinogenicity?
Phthalates



Used as preservatives in foods,
drugs, cosmetics
Possible estrogenic effects
Sunscreen agents


Immunologic effects in mussels
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) = LD50ED50
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
Default Assumption Using Uncertainty Factors
M. Dourson
Ufs
Health
IPCS
Canada
Interhuman
10
10
(3.16 x 3.16) (3.16 x 3.16)
Animal to
10
10
Human
(2.5 x 4.0)
(2.5 x 4.0)
Subchronic
to chronic
LOAEL to
1-100
1-100
NOAEL
Incomplete
database
Modifying
1-10
1-10
Factor
RIVM
ATSDR
EPA
10
10
10
10
10
10
10
NA
 10
10
10
 10
NA
NA
 10
NA
NA
NA
Meek et al., 1994; IPCS, 1994, 2001; Rademaker and Linders, 1994; Pohl and Abdin, 1995;
EPA multiple references
11
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


Infants




Induction/elicitation (e.g., PCN)
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
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
Chemical Mixtures
(Example of Additivity)
Tentatively Identified Compounds at Hobart:
Metaxalone
Codeine
Hydrocodeine
Methadone
Hydrocodeine
Dihydrocodeine
Demerol
Butalbital