Overview and Public Health Implications

1
Overview and Public Health Implications

• Dori R. Germolec
• Toxicology Forum
• National Institute of Environmental Health
  Sciences
• Environmental Immunology Laboratory
• Laboratory of Molecular Toxicology
• National Toxicology Program

2
A System in Balance
Immunosuppression
Immunostimulation
Altered resistance to Infectious Disease and
Neoplasia
Hypersensitivity Autoimmunity
3
Phthalate Effects on the Immune System

• Immune Modulation
• Stimulates self reactivity in autoimmune-prone
  strains of mice
• PPAR ligands appear to stimulate
  anti-inflammatory response (although the data are
  not entirely consistent)
• Induction of IgE and IgG1 antibodies in Balb/c
  mice
• Lack of effects in Mouse IgE test in B6C3F1 mice
• NC in IgE, IL-4, IL-13

• Hypersensitivity
• Occupational exposures associated with asthma,
  rhinitis, respiratory irritancy
• Higher concentrations of specific phthalates
  associated with persistent allergic symptoms in
  children (BBP - rhinitis and eczema DEHP -
  asthma).
• Induction of pro-inflammatory cytokines in human
  cells in vitro

4
Why do certain people develop disease when
exposed to certain drugs or chemicals while
others remain healthy?
Adverse Health Outcome
Exogenous Factors
5
Concordance of Disease in Twin Pairs
Disease
Monozygotic
Dizygotic
Type 1 Diabetes 13-39 3-11 Systemic
Lupus 11-24 0-2 Multiple Sclerosis 9-31 3-5 As
thma 13-51 4-26 Allergy 30-65 7-56
6
Why do certain people develop disease when
exposed to certain drugs or chemicals while
others remain healthy?
Poor Nutrition
Genetic Vulnerability
Adverse Health Outcome
Exogenous Factors
Obesity
7
The Developing Immune System is a Unique Target
for Chemical Insult

• Lineage Development
• Receptor Expression and Rearrangement
• Positive and Negative Selection
• Different pharmacokinetics in embryo, fetuses and
  juveniles versus adults
• Altered ability to recover from environmental
  insult to immune tissues

8
Differential Effects following In Utero Exposures
- Rodent Studies

• Fetal rats are susceptible to TCDD-induced
  suppression of DTH responses at much lower doses
  than adults (Smialowicz, EPA)
• Gestational exposure to TCDD alters fetal
  lymphocyte development and suppresses bone marrow
  hematopoiesis in mice (Gasiewicz, University of
  Rochester)
• Gestational exposures to low levels of lead
  shifts balance to favor Th2 responses (Dietert,
  Cornell)

9
How do we evaluate the potential for drugs or
environmental chemicals to modulate immune
responses?
Product Development
Public Health
Testing And Evaluation
10
Specific Topic Areas in FDA Immunotoxicology
Guidance

• Immunosuppression Effects on the immune system
  that result in decreased immune function
• Immunogenicity Specific immune reactions
  elicited by a drug and/or its metabolites
• Hypersensitivity Immunological sensitization
  due to a drug and/or its metabolites
• Autoimmunity Immune reactions to self-antigens
• Adverse immunostimulation Non-antigen specific
  activation of the immune system

11
Assessing Potential Respiratory Allergens

• Karol test - Inhalation exposure, respiratory
  effects, Guinea pig
• Sarlo approach - Guinea Pig
• In vitro reactivity with protein
• In vivo antibody response
• In vivo reactivity
• Structure Activity
• Mouse IgE test
• Cytokine Profiling

12
EPA Health Effects Test Guidelines
Immunotoxicity(OPPTS 870.7800)
Immunotoxicity testing for pesticide
registration Currently not required in CFR Title
40 Part 158 Required under proposed change (2005
draft testing rule) Assays Antibody
production Phenotypic analysis Natural Killer
(NK) Cell Function Histopatholgy/Organ Wts
13
Immunotoxicology in IRIS Assessments Case-by-Case

• In process
• Phosgene
• Immunosuppression data will be considered in RfC
• Toluene
• Immunosuppression data will be considered in RfD
• Platinum
• Hypersensitivity data will be considered in RfC

• Completed
• Beryllium and related compounds, 1998
• RfC based on
• Chronic Beryllium Disease
• Beryllium-specific lymphocyte proliferation
• Histopathological evidence of granulomas
• Benzene, 2002
• RfC and RfD based on
• Hematotoxicity/Immunotoxicity - Decreased
  lymphocyte counts
• Also noted
• Reduced host resistance
• Decreased antibody responses

14
What can we conclude about the potential for
phthalates to induce or exacerbate allergic
disease?

• Epidemiological studies suggest that phthalate
  exposure may be associated with respiratory
  effects
• In vivo studies in laboratory rodents suggest
  that phthalates have the potential to modulate
  immune response
• What is relevance of the animal data for human
  exposures?
• Doses needed to show modulation of immune
  parameters are much higher than relevant human
  exposures
• Animals models for respiratory allergy and asthma
  may not be predictive of human disease
• Differences between humans and animals in the
  biological effects of PPAR activation

The data appear to indicate that phthalates may
have the potential to induce subtle changes in
immune measures
15
Are Subtle Immune Changes Important?

• NO
• Most immune tests show coefficients of variation
  gt30 in a population
• Immune system has redundancy
• YES
• CD4 drops gt7 increase in developing AIDS
• High incidence of infections in cardiac
  transplants
• High incidence of neoplasia in kidney transplants
• Background incidence of infectious diseases

16
Most Appropriate Model Describing the
Relationship
Between
the Host Resistance and Immune Tests
Host Resistance Test
 
Immune Function Test
 
 
 
PFC
CTL
MLR
ConA
LPS
slg
CD3
CD4
CD8
Thy/BW
L. monocytogenes
L
T
T
L
L
T
T
T
L
T
PYB6 Tumor
L
L
L
L
L
T
L
L
L
L
S. Pneumoniae
T
L
T
L
L
T
L
L
L
N
L linear T- threshold N - neither
 
 
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EPA Immunotoxicology Working Group Goals

• Determine if mild-to-moderate alterations in
  immune measures in the general or susceptible
  populations could lead to adverse effects. Could
  economic social impacts be captured?
• Establish quantitative relationships between
  biomarkers of immune system change and disease in
  humans.
• Prepare a template/example case study.

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Unique Epidemiological Concerns

• Immune Testing
• Enumeration of cells and secretory products
  rather than functional assay
• Test results affected by chronic inflammatory
  conditions (e.g., CVD), acute stress smoking,
  diet, obesity, etc.
• Disease Frequency/Severity
• True frequency of disease outcomes difficult to
  assess
• Self-reported data on is very imprecise,
  especially in cross-sectional or retrospective
  study designs
• Cannot easily control for other factors related
  to frequency of infections or disease episodes

19
N400
Subjects With Infection ()
70 75 80 85 90 95
Observed Adjusted
3-4 5-6 7-8 9-10 11-12
Cohen et al., NEJM, 1991
Psychological-Stress Index
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Increased Frequency of Infections in Children
Exposed to HAH (Dioxins/PCBs)

• Dutch Preschool Children (Weisglas-Kuperus et
  al.,
• EHP 2000)
• Inuit Indians (Dewailly et al., 2000)
• Michigan study (Karmus et al., Arch Envir.
  Hlth, 2001)
• Japan-Yusho (Hishito et al., EHP, 1985)
• China- Yu-Cheng (Yu et al., Chemosphere, 1998)

21
Case Studies Upper Respiratory Infections
(Influenza Pneumonia)

• Death rate 23.0 per 100,000
• Infants 6.5 per 100,000 live births
• Elderly (some est. at 95) 12.3 per 100,000
• Economic Cost of Illness approach
• Deaths, hospitalizations, outpatient or emergency
  room visits lost-work days (wages)

22
Cost Estimates (in Billions) of Infectious
Diseases for 2000
Illness Total Cost Direct Indirect (medical) (lo
st productivity)
Pneumonia Influenza 25.6 18.6 7.0 Otitis
Media 5.0 2.9 2.1 HIV/AIDS 28.9 13.4 15.5 Septicem
ia 7.2 4.9 2.3 Respiratory
Distress 4.1 3.2 0.9 Syndrome
sources USDHHS and NIH
23
Final Thoughts
This may be a case of hazard identification
versus risk The available data suggest that if a
large enough population is exposed and that the
challenge dose or frequency of exposure to
antigen is sufficient, small changes in immune
responses could increase the background incidence
and burden of disease in the human population.