Effect of Genetic Differences on Levels of Water Disinfection Byproducts in Blood After Showering
Condition: Normal Physiology
Study type: Observational

Summary: 
      This study will examine whether genetic differences among individuals affect blood levels of
      certain chemicals called DBPs after showering. Chemicals such as chlorine and ozone are used
      to kill germs in water. These chemicals may react with organic matter in the water and form
      other chemicals called disinfection byproducts, or DBPs. Although people are usually exposed
      to DBPs by drinking tap water, these chemicals may also penetrate the body during showering.
      This study will see whether the levels of DBPs after showering vary among individuals
      depending on differences in genes that code for enzymes called GSTT1, CYP2D6, and CYP2E1,
      which break down DBPs. This study, sponsored by the Centers for Disease Control and
      Prevention and the National Institutes of Health, is conducted at the University of
      Pittsburgh's Center for Clinical Pharmacology.

      Healthy adults between 18 and 45 years of age who do not smoke cigarettes and are not taking
      any medicines may be eligible for this study. Candidates are screened with a medical history
      and blood and urine tests. Participants are given a diary to record the foods they eat and
      how much water they drink during the 2 days before their study appointment. The following
      activities are scheduled on the appointment day:

        -  Measurements of blood pressure, height, and weight, and pregnancy test for women

        -  Questions about alcohol consumed and medications taken in the last 48 hours

        -  Review of food and water diary

        -  Interview for demographic information (name, address, date of birth, etc.) and other
           information, such as sex, height, weight. Subjects are also asked about anything, such
           as exercise, that might affect their breathing, since breathing problems are a rare side
           effect of chlorzoxazone, a drug used in this study.

        -  Urine sample collection

        -  Blood draw and insertion of a small catheter (plastic tube) to allow for additional
           blood draws during the test procedure without having repeated needle sticks

        -  10-minute shower in a private bathroom

        -  Blood sample collection 10 minutes after the shower and again at 30 minutes after the
           shower

        -  Dose of chlorzoxazone (a drug used to treat muscle pain)

        -  Interview about subject's exposure to water

        -  Light breakfast

        -  Blood and urine collections 2 hours after the chlorzoxazone dose

        -  Lunch

        -  Observation for drug side effects for 2 hours, or longer if needed

      Seven blood samples totaling 75 milliliters (about 5 tablespoonfuls) of blood are collected
      during this study. The blood is tested for chemicals called trihalomethanes to see how they
      are broken down. The urine samples are tested for chemicals called haloacetic acids, which
      are found in tap water after it has been treated with chlorine.
    

Detailed description: 
      Disinfection byproducts in drinking water (DBP) are inadvertently created when chlorine
      interacts with organic compounds in the untreated water. DBP have been implicated in elevated
      risk of several types of cancer. Until recently, ingestion was considered to be the major
      route of exposure. However, an NCI collaborative study in Spain is now showing a link between
      bladder cancer and exposure to DBP in water during showering or bathing. However, little is
      known of the mechanisms of action. Almost all drinking water disinfected with chlorine
      contains measurable levels of DBP. The DBP found in greatest concentration are the
      trihalomethanes [(THM); chloroform, bromoform, bromodichloromethane, and
      dibromochloromethane]. Previously, our collaborators from the CDC measured changes in blood
      THM levels after showering and bathing, and ingesting water. Showering resulted in the
      largest increases, with a wide range in the increase among subjects with similar exposures.
      Enzyme variants due to genetic polymorphisms may be responsible for these differences.

      We plan to assess the association between the presence of enzyme variants (genetic
      polymorphisms) and the increase of trihalomethanes in the blood of people exposed to DBP
      while showering. The study will be conducted at the General Clinical Research Center (GCRC),
      Center for Clinical Pharmacology (CCP), University of Pittsburgh, Dr. Robert Branch,
      Director. Approximately 250 volunteers will be identified from Dr. Branch's ongoing research
      program. These subjects will have been pre-screened with a normal standard blood panel and
      for genetic polymorphisms of interest. From this pool of pre-screened individuals, we will
      recruit approximately 100 people who have enzyme variants of differing activity.

      We will ask the 100 volunteers to provide seven 10-mL blood samples and two urine samples,
      and take a 10-minute shower at the study site (the CCP in Pittsburgh, PA). Blood samples will
      be analyzed for trihalomethane concentrations, and red blood cell enzyme activities. To study
      the activity of the enzyme CYP2E1, we will administer a single dose of chlorzoxazone, a
      muscle relaxant metabolized by this enzyme. We will measure enzyme activity by analyzing
      blood samples collected 2 hours post-administration. We will conduct a brief interview with
      each volunteer to obtain demographic and other information that might impact the dose of THM.
      We will collect ambient air samples before, during and after showering for each participant
      and analyze them for levels of THMs. A water sample will be collected during showering and
      analyzed for levels of THM and haloacetic acids. We will ask 10 randomly selected study
      subjects to repeat study activities for quality control purposes.

      Levels of THM in blood before and after showering, and the rate of decrease in blood
      concentration, will be analyzed with respect to the presence of genetic polymorphisms for
      selected enzymes, or their phenotypic activity. Blood THM levels will also be compared with
      various demographic and physiologic measurements. To test intra-individual variation in
      several measures, ten randomly selected participants (stratified by sex, i.e. 5 males and 5
      females) will be asked to conduct the study twice, with the two study appointments separated
      by at least a week.
    

Observational model: Other
Time perspective: Cross-Sectional
Sampling method: Non-Probability Sample
Study population: 
        convenience sample of individuals recruited at the University of Pittsburgh.
      
Keywords: Disinfection byproducts; Genetic Variation; Trihalomethanes