Childhood Asthma/Tobacco Smoke

Introduction

Characteristics

Fate and Transport

Exposure Pathway

Methods for Monitoring in the Environment

Methods for Measuring Human Exposure

Strategies for Preventing or Controlling Exposure


Respiratory Harmful Effects

Deposition, Absorption, and Metabolism

Dose-Response Relationship

Organ Sites of Toxicity

Biomarkers

Risk Assessment/Risk Management Considerations

References

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Sites of Toxicity

Respiratory System


http://www2.merriam-webster.com/mw/art/respirat.htm

1 nostril, 2 nose, 3 nasal cavity, 4 superior nasal concha, 5 middle nasal concha, 6 inferior nasal concha, 7 nasopharynx, 8 oropharynx, 9 laryngopharynx (7 through 9 comprise the pharynx), 10 larynx, 11 trachea, 12 bronchus, 13 lung, 14 thyroid cartilage


EVIDENCE FROM ANIMAL STUDIES
Pulmonary Effects
Enzyme Activity

Pulmonary Effects in Adult Animals
Numerous animal studies have examined the effects of exposure to sidestream smoke (SS) on the adult animal lung

Studies indicating minimal lung effects, even at longer durations of exposure

  • A series of studies were conducted by Coggins and colleagues on the effects of different SS concentrations and duration on the adult rat lung (1992, 1993, and 1995):
    • three concentrations of SS: 0.1, 1.0, and 10 mg/m3 of total suspended particulates (TSPs). Exposure was 6 hours/day, 5 days/week for 14 days and 90 days
    • The only notable change was in the nasal turbinates (#4-6 on diagram of respiratory system above) of rats exposed for 90 days to the highest concentration of SS. This change was characterized by slight epithelial hyperplasia in the nasal cavity
      • epithelium: a membranous cellular tissue that covers a free surface or lines a tube or cavity of an animal body and serves especially to enclose and protect the other parts of the body, to produce secretions and excretions, and to function in assimilation
    • these studies revealed a NOAEL for histopathology, cell replication and DNA adduct formation to be at least 1 mg/m3 of TSPs.
  • von Meyerinck et al. (1989) studied the effects of long-term exposure on the adult rat and hamster lung:
    • concentration/duration of exposure: 4 mg/m3 of TSPs for 90 days
    • No signs of smoke toxicity were observed in the hamster respiratory tract; in rats, hyperplasia and metaplasia in the epithelium of the nasal turbinates observed.

Studies indicating lung effects at short-term durations of exposure

  • Witschi & Rajini (1994) conducted two studies examining the effects of short-term SS exposure
    • A/J mice exposed to 1 mg/m3 of TSPs experienced enhanced cell proliferation in the airway epithelia after only five days of exposure.
    • Syrian golden hamsters exposed to 1 mg/m3 of TSPs for up to three weeks also experienced increased cell proliferation in the nasal epithelia.
    • These studies would contradict the applicability of Coggins et al.’s NOAEL of 1 mg/m3 in hamsters and A/J mice.

Thus, there is conflicting evidence revealed regarding SS concentration and duration necessary to induce pulmonary effects in rats, mice and hamsters (see Witschi, Joad & Pinkerton review, 1997), as well as the appropriate NOAEL.

Effects on Enzyme Activity involved in Lung Maturation in Animals

Several studies have investigated early postnatal effects of SS exposure on enzyme activity (specifically cytochrome P450) and lung maturation in rats

  • Ji and colleagues (1994) examined the effects of SS on lung maturation in the developing postnatal rat lung
    • concentration/duration of exposure: 1mg/m3 of TSPs, 6 hours/day, 5 days/week
    • results indicate that exposure to SS from birth has numerous effects
      • interference of epithelial cell proliferation
      • increased bronchiolar expression of NADPH reductase
      • acceleration and maintenance of cytochrome P450 isozyme 1A1 protein expression in clara cells
      • clara cells: nonciliated bronchiolar epithelial cells, characterized by electron-dense secretory granules and large amount of smooth endoplasmic reticulum in their cytoplasm (Witschi et al., 1997)
  • Gebremichael and colleagues (1995) further examined the influence of SS on cytochrome P450 monooxygenases 1A1 and 2B1 in the developing rat lung and liver
    • concentration/duration of exposure: 1mg/m3 of TSPs from birth to 7, 14, 21, 50 and 100 days of age
    • results indicate that P4501A1 and P4502B1 develop at different rates in the rat lung and liver
    • exposure to SS significantly increased P4501A1 activity in the lung at all ages

Witschi et al. (1997) hypothesize that the significant effect of SS on enzyme activity involved in lung maturation is likely due to the effects on clara cells. The presence of the cytochrome P450 monooxygenase system in clara cells appears to play an important role in the toxicity of SS. These cell populations are involved in the metabolism of chemicals by the lung and have the ability to generate reactive metabolites. Various components of ETS may be metabolized by the P450 system, which can result in increased or decreased toxicity of parent compounds. Some constituents of ETS may act as inducers or inhibitors of P450 isoenzymes 1A1 and 2B. Thus, clara cells may be particularly vulnerable to damage by multiple toxicants present in ETS.

In humans, Boers et al. (1999) has demonstrated that clara cells substantially contribute to cell renewal in typically functioning airway epithelium. The number of overall clara cells is reduced in smokers, as are certain proteins secreted by clara cells (Shijubo et. al., 1997).