Toxicokinetic Study of Lambda-cyhalothrin Biomarkers of Exposure
Condition: Exposure to Pollution
Study type: Interventional

Summary: 
      Exposure to pyrethroid pesticides is a growing concern in the workplace especially since they
      are also present in the diet of the general population. It is important to monitor human
      exposure to these contaminants. Exposure to pyrethroids may occur by multiple routes of
      exposure (oral, inhalation and dermal), such that it is difficult to assess absorbed doses
      from external exposure assessments. Biological monitoring, which consists of measuring
      urinary metabolites, is now recognized by the scientific community as a preferred approach to
      assess exposure to this type of compound. These metabolites are biotransformation products
      produced in the human body from the exposure compounds. However, interpretation of these
      biological monitoring data requires a proper knowledge of the kinetic behavior and thus the
      fate of the substance of interest in the human body in order to link levels of biomarkers in
      individuals to actual absorbed doses. Human kinetic data are still poorly documented in the
      case of pyrethroids. The study in volunteers exposed to pyrethroids in controlled conditions
      will allow acquiring new urinary and blood profiles to refine and address uncertainties in
      the toxicokinetics of lambda-cyhalothrin following oral and dermal exposure. Those data will
      serve to build a toxicokinetic model to predict absorbed doses in workers from urinary
      metabolite measurements and therefore better assess health risks.
    

Detailed description: 
      Lambda-cyhalothrin is a synthetic pyrethroid pesticide widely used in Quebec to fight against
      pests in vegetable crops. In recent years, this pyrethroid has become one of the most used
      insecticides in these crops. However, there is a paucity of data on the biological behavior
      of this molecule in humans. Given the extensive use of this pyrethroid, it becomes essential
      to develop tools to properly assess exposure among workers largely in contact with pesticides
      during spraying or work in treated areas. Biological monitoring, which consists of measuring
      urinary metabolites is considered a preferred approach to evaluate absorbed doses of this
      type of product in the workplace, given the potentially combined exposure through the
      respiratory, dermal and oral routes. However, interpretation of biological monitoring data
      requires a good knowledge of the kinetic behavior of the substance of interest in the human
      body, to link biomarker levels among workers to actual absorbed doses. The overall objective
      of this project is to address the lack of knowledge on the toxicokinetics of biomarkers of
      exposure to lambda-cyhalothrin in humans for a better interpretation of routine biomonitoring
      data and hence health risks in exposed workers. First, a controlled kinetic study will be
      conducted in volunteers exposed acutely to a low oral dose of lambda-cyhalothrin (oral
      reference dose) followed by a cutaneous dose (of lambda-cyhalothrin formulation used by
      sprayers). The protocol will be similar to a previous one used by our team for toxicokinetic
      assessment of other pesticides. Secondly, a toxicokinetic model will be developed to simulate
      the kinetics of biomarkers of exposure to lambda-cyhalothrin, using data from the controlled
      kinetic study and based on a previous toxicokinetic model for related pyrethroids.

      More specifically, volunteers will be exposed orally to 0.025 mg/kg body weight of
      lambda-cyhalothrin (single oral dosing). According to recent health risk assessment by the US
      Environmental Protection Agency (US EPA), volunteers should not incur any adverse effects
      relating to such dosing. Three weeks following oral dosing (to allow complete elimination of
      the compound from the body), the same volunteers will be exposed dermally to a
      lambda-cyhalothrin-based formulation used on crops. The formulation will be applied on a
      40cm2 surface of the forearm at a concentration corresponding to the one used in the
      workplace (Matador 120EC). The treated area will not be washed for a period of 6 h. This type
      of application will be similar to that of exposed workers. Urinary and blood measurements of
      specific biomarkers of exposure to these insecticides will be performed. These biomarkers of
      exposure are already known from other studies and have been shown to be good bioindicators of
      exposure to pyrethroids. The kinetic profile will serve to link absorbed doses to blood and
      urinary concentrations of metabolites through time. Personal information on health status,
      diet and lifestyle will be documented. A total of 7 volunteers will spend a full day at the
      University during which they will be exposed to a low dose of pesticide. Blood and urinary
      samples will be collected. Four short visits of one hour will be needed for blood
      collections. Every urine void for a period of 84 hours will be collected in a different
      bottle. This whole process will be repeated twice to test two routes of exposure to this
      insecticide, oral (swallowed) and dermal (applied to the forearm).

      The study in volunteers exposed to lambda-cyhalothrin in controlled conditions will allow
      acquiring new urinary and blood metabolite profiles to better understand their kinetic
      behavior and essential biological determinants of the observed profiles. These data can then
      be used in a toxicokinetic model to predict the main routes of exposure and associated
      absorbed doses in workers exposed to formulations containing lambda-cyhalothrin.
    

Intervention name(s): Exposure
Intervention type(s): Other
Intervention description(s): Oral exposure: 0,025 mg/kg bw dissolved in oil, on day 1, with blood withdrawn on days 2,3,4.
Dermal exposure: 145 µl of commercial formulation (0,25 mg/kg bw) on 40 cm2 of forearm skin for 6 hours, on day 28, with blood withdrawn on days 29,30,31.
Allocation: Non-Randomized
Intervention model: Crossover Assignment
Masking: Single (Participant)
Primary purpose: Basic Science
Keywords: Pyrethroids; Lambda-cyhalothrin; Biomarkers; Toxicokinetics