Assessment

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Assessment Control of Hazards in the
Workplace Reproductive Risks
Ellen C. Faria, Ph.D., DABT Principal
Occupational Toxicologist JJ Pharmaceutical
Research Development NJAIHA 16 October 2008
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Objectives

• General understanding of occupational toxicology
• Hazard assessments (PBOELs)?
• Controls (OELs)?
• How OT, IH OccHealth Teams collaborate
• Reproductive developmental risk management
  program/tools

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Minimizing Risk in the Workplace
Workplace Evaluation (Risk)?
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Occupational Toxicology 101
All substances are poisons, there is none which
is not a poison. The right dose differentiates a
poison and a remedy. Paracelsus (1493-1541)?
Response
Dose

• ALL chemicals have the ability to be toxic in
  high enough amounts.
• Hazard (toxicity) - the inherent ability for a
  chemical to produce adverse effects in a
  biological system.
• Risk - the probability that a substance will
  produce harm under certain conditions of
  use/exposure.

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Occupational Toxicology 101

• Active pharmaceutical ingredients (APIs) are
  different from other typical laboratory chemicals
• Designed to produce an effect (receptors,
  enzymes) at very low concentrations
• Goal
• Identify health hazards
• Prevent adverse effects in employees
• Identify the workplace exposure level which
  minimizes risk to the employees
• Prevent over-exposure

Sedation
Pain relief
100
response ()?
50
0
Dose
NOELs
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Performance-based occupational exposure limit
(PBOEL) categories

• A classification system used to assign materials
  into one of several health hazard categories of
  increasing severity based upon their inherent
  pharmacological and toxicological properties.

• These categories correspond to predefined
  strategies or control philosophies known to
  provide the necessary degree of control to
  protect employees and the environment. (open ? ?
  closed handling)?

Therefore The more severe the
hazard. the more stringent the containment
to achieve acceptable level of risk.

• Naumann, et. al. Performance-Based Exposure
  Control Limits for Active Pharmaceutical
  Ingredients. American Industrial Hygiene
  Association Journal. 5733-42 (1996).

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PBOEL Category General Criteria
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Containment philosophies
Closed Systems
Typical PBOEL Clinical Dose
Isolation/Barrier/ Administrative controls
4 3A/B 2 1
lt 0.01 mg/day
Isolation/Barrier
Directional Laminar Flow Laminar Flow
Local Exhaust General Exhaust
gt100 mg/day
Open Systems
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Control bands

• Typical airborne levels allowed (target low
  end of band)?
• Category 1 100 - 3000 ?g/m3
• Category 2 20 - 100 ?g/m3
• Category 3A 5 - 20 ?g/m3
• Category 3B 500 ng/m3 - 5 ?g/m3
• Category 4 lt 500 ng/m3

Unstudied compounds Default PBOEL Category
3A With the exception of several therapeutic
classes (PBOEL Category 4 anti-neoplastics,
anti-arrhythmics)?
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Drug Development Process
Years
Years
6 months- 2/3 years
OEL- Occupational Exposure Limit PBOEL-
Performance-based occupational exposure
limit ASL- Accepted surface limit (wipe
limit)? API- Active pharmaceutical
ingredient IPI- Isolated Process intermediates
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Occupational Exposure Limits (OELs)
ADI (?g/day) NOEL or LOEL (?g/kg/day) x BW
(kg)?
S x UF x ?
Lowest clinically active dose (?g/day)?
S x UF x ? OEL (?g/m3)   ADI
(?g/day)? V (m3/day)?
ADI Allowable daily intake via any
route NOEL No-Observed-Effect-Level BW
Average human body weight (50 kg)? S
Pharmacokinetics (half-life and
accumulation)? UF Uncertainty
Factors ? Used to adjust the
absorption of a compound such that it equals 100
via inhalation. OEL Airborne conc.
which will not result in adverse effects in most
healthy workers (8 hrs X 40 yrs)? V
Volume of air breathed in an 8-hour workday
(10 m3)?

• Sargent, Edward V. and G. David Kirk
  "Establishing Airborne Control Limits in the
  Pharmaceutical Industry. American Industrial
  Hygiene Association Journal. 49(6)309-313
  (1988).

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Occupational Exposure Limits (OELs)?

• Data Considered
• Therapeutic class pharmacological potency
• Toxicity/safety clinical data
• Peer-review approval
• Approved by consensus
• Benchmark with industry experts
• Documented OEL Monograph (scientific document)?
• Uncertainties accounted for
• Susceptibilities/differences between individuals
• Differences between species (animal to human)?
• Short-term long-term exposures
• LOEL to NOEL extrapolation
• Route to route extrapolation
• Modifying Factors
• Severity of toxicity (i.e. irreversible effects)?
• Database incompleteness

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Notations

• Repro notation (RReproductive Effector)?
• highlights the potential for an agent to cause
  damage to the reproductive system of males and
  females and damage to an unborn child.
• SKIN notation
• highlights the potential that an agent has for
  significant absorption via the skin (dermal
  absorption).
• DSEN notation
• highlights the potential for an agent to cause
  delayed allergic skin reactions.
• RSEN notation
• highlights the potential for an agent to be a
  respiratory sensitizer (i.e. occupational
  asthma).

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Risk Assessment Management
Signs/symptoms, Surveillance Medical history
Hazard identification
Occupational Toxicology
Occupational Health
RA
Exposure Assessment
Industrial Hygiene
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Hazard Risk Assessments in Practice
Reproductive/Developmental Assessments
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Why such a concern?
Pregnancy Outcomes- U.S. (2005)?
Adverse Effects

• post-implantation loss
• major birth defects (birth)?
• major birth defects (gt1 yr)?
• minor birth defects
• low birth weight
• infant mortality
• abn. neurological function

31 4 7 14 7 2 17
lt 50 normal infant 65 unknown etiology
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Why such a concern?

• Birth defects leading cause of infant mortality
  (US)?
• 17 US children developmental disorders
• Infertility gt 2 million couples (US)?
• Decreasing sperm counts
• Susceptibility
• Cell Division - Mitosis Meiosis
• Integrated physiological function
• Multiple targets, some more sensitive than others
  at different times.

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Male Reproductive Toxicology (M)?

• Targets
• Neuroendocrine system
• Accessory sex glands
• Spermatogenesis
• Sexual function

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Male Reproductive Toxicology (M)?

• Moral, ethical and legal issues collection of
  information poor
• experimental assays are limited (sperm output,
  fertility measurement of hormone levels)?
• Not examined in routine autopsies
• Chemicals detected by semen analysis does not
  indicate toxicity
• Damage to the testis can cause recessive
  mutations in germ cells that may accumulate and
  go undetected for generations
• Unlike the ovaries, cell division in the testis
  is continuous
• Testicular cancer not rare among young adult men
  (US) rate ?

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Female Reproductive Toxicology (F)?

• Targets
• Post-ovarian Structures Processes
• Neuroendocrine system
• Ovarian Function
• Fertilization/Implantation

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Female Reproductive Toxicology (F)?

• Contraceptives difficult to assess reproductive
  toxins in human females
• Targets each has a specialized function under
  influence of the neuroendocrine system
• Ovaries are especially sensitive to insult have
  dual functions produce oocytes and secrete
  steroid hormones
• Oogenesis (egg production) starts before birth
  (first trimester)?
• Large number of dividing germ cells
• viable eggs is limited
• Birth- 2 million eggs
• Puberty- 30 to 40 thousand
• Post-maturation- 400
• Damaged oocytes cannot be replaced causing
  sterility
• If chemical or radiation injury causes
  chromosomal damage, the damage lasts a lifetime

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Developmental Toxicology (D)?

• Manifestations
• growth retardation
• functional impairment
• structural malformations
• embryo lethality
• Factors critical to toxicity
• Nature/inherent properties of toxin
• Level of exposure
• TIMING of exposure (organogenesis)?
• Numerous radiation, infections, maternal
  imbalances, drugs and chemicals

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Developmental Toxicology (D)?

• Damaged ovarian germ cells mutations that can
  lead to developmental disorders or cancer
• Embryonal/fetal damage ? can produce various
  deformities that appear later rather than sooner
• Pregnancy stage determines the outcome
• Various organs have different periods of
  development and sensitivity

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Lactation (L)?

• Quality production of breast milk
• Lipid soluble compounds accumulate in breast
  tissue and may be expressed in breast milk
• Nursing infants may be exposed to xenobiotics
• Methylene chloride, ETOH, heavy metals, KI, etc.
• Cannot tell if toxic to nursing infant
• Can only tell if it is present in breast milk

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Occupational Reproductive/Developmental Health
Hazard Program
Employee
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Occupational Reproductive/Developmental Health
Hazard Program

• Professionals (IH, Occ Tox Occ Health)?
• Implement programs regulations
• Assess reproductive risks in timely manner
• Amount, route, timing, duration, and frequency of
  exposure
• Recommend risk management steps
• Communicate

• Employee
• Understand and participate in Corp programs
  adhere to regulations
• Understand benefits
• Adhere to recommendations
• Communicate

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Occupational Reproductive/Developmental Health
Hazard Program

• Management
• Assure recommendations are implemented
• Cooperate with employee professionals
• Communicate

• Human Resources
• Ensure job security
• Ease implementation of recommendations
• Implement procedures for conflict resolution
• Understand the RA process
• Assure appropriate documentation
• Communicate

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Occupational Toxicology

• Priority to determine hazards
• Work with Occupational Health IH
• Utilize sound (peer-reviewed) data from reliable
  resources
• Relevance to human toxicity
• Dose-response
• Identify classify toxicants to be easily
  understood
• Put potential risk into appropriate perspective

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Resources

• Reprotox, Shepards, Reprotext
• National Library of Medicine Databases (NIH)?
• Developmental Repro. Tox (DART)?
• Environ. Teratology Info. Center Backfile
  (ETICBACK)?
• Hazardous Substance Databank (HSDB)?
• Reg. of Tox Effects Chem. Sub. (RTECS)?
• PubMed journals
• LactMed
• Books (Lewis, Shepard, Schardein)?

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Professional Judgment

• Methanol
• Pregnant rats exposed to 20,000 ppm methanol in
  air during gestation experienced a significant
  increase in skeletal, urinary, and cardiovascular
  defects in the fetuses when compared to unexposed
  controls (Nelson et al, 1985).
• Ethidium bromide
• This agent intercalates DNA strands and was
  mutagenic in a number of test systems (1,2). It
  is possible that nucleic acid alterations induced
  by ethidium make cells more susceptible to the
  effects of other cytotoxicants. Such an effect of
  ethidium has been demonstrated with respect to
  bleomycin (3), but not with respect to x ray (4).
  There are few studies on the potential
  embryotoxicity of ethidium. This agent is capable
  of arresting growth and development in early sea
  urchin embryos (5). Ethidium tested positive in
  the FETAX assay, a test system using toad
  embryos. The concentration of ethidium resulting
  in death of half the embryos was 0.05 mg/mL and
  the concentration resulting in malformation of
  half the embryos was 0.035 mg/mL (6). Neither the
  mutagenicity data nor the FETAX assay can be
  considered predictive of human response. We have
  not located any data on human reproductive or
  lactation effects of ethidium.
• Thalidomide
• Human teratogen, but a weak teratogen in
  animals.
• Aspirin
• Strong rodent teratogen, but no such effect on
  humans.

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Tool Identifying Potential Toxicants
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Criteria for classification 1

• Existing data indicates that this agent has the
  potential to cause
• fetal harm (D1)?
• adverse reproductive effects in females (F1)?
• adverse reproductive effects in males (M1)?
• At dose levels lt potential workplace exposures
• Therefore exposure should eliminate

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Criteria for classification 2

• Existing data indicates that this agent has the
  potential to cause
• fetal harm (D2)?
• adverse reproductive effects in females (F2)?
• adverse reproductive effects in males (M2)?
• At dose levels gtgtgt potential workplace exposures
• Therefore exposure minimized

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Criteria for classification 3

• Existing data indicates that this agent does not
  have the potential to cause
• fetal harm (D3)?
• adverse reproductive effects in females (F3)?
• adverse reproductive effects in males (M3)?
• At dose levels potential workplace exposures
• Therefore exposure safe chemical handling
  procedures

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Criteria for classification 4

• No data exists on the potential for this agent to
  cause
• fetal harm (D4)?
• adverse reproductive effects in females (F4)?
• adverse reproductive effects in males (M4)?
• Safe workplace exposures are unknown
• Therefore exposure minimized (PBOEL system)?

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Challenges

• Hazard risk assessment programs
• Lack of SMEs (interpret information ?)?
• Workers taking unnecessary risks
• Particular susceptibility- repro organs
  developmental
• Existing historical taboo about early pregnancy
• Unreliable resources of information used for
  hazard ID
• No team approach to assessments recommendations
  (integration of disciplines)?
• Lack of communication understanding between
  groups
• Lack of clarity of responsibilities
• Resistance to make decisions alone

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Summary

• Develop internal policies/programs
• Document hazard risk assessments
• Dynamic process
• Team approach in risk assessment management
• Training (hazards, risks, confidentiality,
  programs, benefits, etc.)?
• Timing of evaluations
• Reliable resources

• Communication is Key !!!