Clinical and laboratory observation

Urine cotinine excretion in neonates exposed to tobacco smoke products in utero

The widespread use and high abuse liability of tobacco products has received considerable public health attention, in particular for youth, who are vulnerable to nicotine addiction. In this study, adult and adolescent squirrel monkeys were used to evaluate age-related metabolism and pharmacokinetics of nicotine after intravenous administration. A physiologically-based pharmacokinetic (PBPK) model was created to characterize the pharmacokinetic behaviors of nicotine and its metabolites, cotinine, trans-3′-hydroxycotinine (3′-OH cotinine), and trans-3′-hydroxycotinine glucuronide (3′-OH cotinine glucuronide) for both adult and adolescent squirrel monkeys. The PBPK nicotine model was first calibrated for adult squirrel monkeys utilizing in vitro nicotine metabolic data, plasma concentration-time profiles and cumulative urinary excretion data for nicotine and metabolites. Further model refinement was conducted when the calibrated adult model was scaled to the adolescents, because adolescents appeared to clear nicotine and cotinine more rapidly relative to adults. More specifically, the resultant model parameters representing systemic clearance of nicotine and cotinine for adolescent monkeys were approximately two- to three-fold of the adult values on a per body weight basis. The nonhuman primate PBPK model in general captured experimental observations that were used for both model calibration and evaluation, with acceptable performance metrics for precision and bias. The model also identified differences in nicotine pharmacokinetics between adolescent and adult nonhuman primates which might also be present in humans.

To determine whether perinatal smoking exposure is associated with gastroesophageal reflux (GER)-related changes in sleep-wakefulness states in neonates.

Thirty-one neonates, referred for the investigation of suspected GER, were recruited and underwent multichannel impedance–pH monitoring and synchronized 8- to 12-hour polysomnography. The infants' exposure to tobacco smoke was estimated by means of a urine cotinine assay. The total number, frequency (h⁻¹), and mean duration (minutes) of GER-pH (reflux events detected by the pH electrode only) and GER-imp (reflux events with bolus movement detected by impedance) events were determined. Intergroup differences (smoking-exposed group vs nonexposed group) were probed with nonparametric, unpaired Mann–Whitney U tests. A χ² test was used to assess a possible intergroup difference in bolus retrograde migration during GER-imp events.

According to the urine cotinine assay, 21 of the 31 neonates had been exposed to cigarette smoke during the perinatal period. The number (and frequency) of GER-imp was significantly greater (P = .016) in the exposed group (29 [0-90]) than in the nonexposed group (12 [2-35]). Migration of the esophageal bolus from the distal segment to the most proximal segment was significantly more frequent (P = .016) in the exposed group (83% of GER) than in the nonexposed group (41%). The GER pattern associated with smoking exposure was particularly obvious during Rapid eye movement sleep.

The more frequent occurrence and greater proximal migration of GER-imp in the smoking-exposed group (especially during rapid eye movement sleep) may have clinical relevance. Smoking exposure is a preventable risk factor for limiting the occurrence of GER in neonates.

Although a single measurement of urinary cotinine is often used for biological monitoring, the validity of this measurement for estimating long-term exposure has not been well evaluated. The purpose of this study was to determine the efficacy of using a single measurement per person to estimate long-term smoking exposure in an elderly population. Analysis was conducted using a cohort of elderly subjects for whom multiple urinary cotinine measurements had been collected over eight weeks. The mixed-effects model of urinary cotinine indicated that interpersonal variability was greater than temporal variability. The efficacy of using single measurements to track the mean long-term exposure of a population is supported by the relatively consistent population averages. The classification of high and low exposure groups using a single measurement or using eight measurements produced similar group distributions. When using cut-off levels of 20 and 100 μg cotinine/g creatinine, 9.3% and 5.6% of individual exposures were misclassified, respectively, when using a single measurement. Urinary cotinine can be a useful biomarker for characterizing exposure to tobacco smoke. Although the incidence of misclassification decreased with an increase in the number of measurements, a single measurement of the urinary cotinine level may accurately represent long-term exposure to tobacco smoke.

The effects of maternal cigarette smoking during pregnancy on structural chromosome aberrations were evaluated in peripheral lymphocytes from 239 mothers and their 241 newborns to determine whether smoking during pregnancy, genetic susceptibility, and race are associated with chromosome aberrations including translocations. Demographic information and cigarette smoking data were obtained via questionnaire. There were 119 Caucasian Americans, 118 African Americans, and 2 Asian Americans. The average maternal age was 24.9 ± 5.8 (mean ± S.D.) years. Thirty-nine percent of the Caucasian Americans and 45.4% of the African Americans self-reported that they were active smokers during the index pregnancy. The average number of cigarettes smoked per day was 2.65 ± 5.75 and 1.37 ± 3.17 for Caucasian and African American mothers, respectively. Peripheral blood lymphocytes from the mother and from the fetal side of the placenta were evaluated for chromosome aberrations by whole chromosome painting. Aliquots from the same blood samples were also used to assess genetic susceptibility with an in vitro bleomycin challenge assay. Spontaneous translocation frequencies in both maternal and newborn lymphocytes were not associated with cigarette smoking, socioeconomic status, or education. The absence of a smoking effect may be attributable to the low level of cigarette usage in these subjects. The average bleomycin-induced damage in the maternal and newborn populations was 0.37 ± 0.27 and 0.15 ± 0.14 breaks per cell, respectively, a difference that was highly significant (p < 0.0001). In newborns there was a positive association between bleomycin sensitivity and the frequencies of aberrations as measured by chromosome painting: p ≤ 0.0007 for dicentrics and fragments, and p ≤ 0.002 for translocations. Caucasian American newborns demonstrated a significant association between dicentrics and fragments as measured by painting, and bleomycin sensitivity (p ≤ 0.0002), but no such association was observed for African American newborns. The results of this study indicate that while differences were observed between African Americans and Caucasian Americans, race does not appear to be a major contributor to chromosome damage in newborns or their mothers. However, peripheral lymphocytes in pregnant women are more susceptible to genetic damage than peripheral lymphocytes in newborns.

Nicotine is rapidly and extensively metabolized in humans. We present an analytical method to simultaneously quantify nicotine, cotinine, norcotinine, and trans-3′-hydroxycotinine in human oral fluid. Solid phase extraction (SPE) and GC/MS/EI with selected ion monitoring (SIM) were utilized. Linearity ranged from 5 to 1000 ng/mL of oral fluid; correlation coefficients for calibration curves were >0.99. Recoveries were 90–115% nicotine, 76–117% cotinine, 88–101% norcotinine, and 67–77% trans-3′-hydroxycotinine. Intra-assay precision and accuracy ranged from 1.6 to 5.7% and 1.6 to 17.8%, respectively. Inter-assay precision and accuracy ranged from 4.3 to 10.2% and 0 to 12.8%, respectively. Suitable precision and accuracy were achieved for the simultaneous determination of nicotine and three metabolites in the oral fluid of smokers. This assay is applicable to pharmacokinetic studies of nicotine, cotinine, and trans-3′-hydroxycotinine from tobacco smokers and can be utilized for routine monitoring of tobacco smoke exposure. 3-Hydroxycotinine requires additional investigation to determine its usefulness as a biomarker for tobacco smoke exposure.

Objective: To determine whether infants born to smoking mothers have an abnormal respiratory drive and a blunted ventilatory response to hypoxia. Study design: Sixty-four healthy infants, aged 2 to 24 months, were classified into smoking (n = 19) or non-smoking (n = 45) groups based on maternal smoking habits. Resting ventilation, lung function, and mouth pressure 100 milliseconds after an airway occlusion at the onset of inspiration (P_0.1 ) were measured. The ventilatory response to hypoxia was assessed in 15 infants (6 in the smoking group and 9 in the non-smoking group) while breathing 14% oxygen. Results: Respiratory drive (P_0.1 = 4.9 ± 1.3 cm H₂ O) was lower in infants in the smoking group compared with those in the non-smoking group (P_0.1 = 5.9 ± 1.2 cm H₂ O) (P < .05). The time to peak tidal expiratory flow (tPTEF) was also shorter (0.25 ± 0.04 seconds vs 0.32 ± 0.09 seconds, P < .05). Infants born to non-smoking mothers showed a significant ventilatory response to hypoxia and a 24.6% increase in P_0.1 . Infants in the smoking group showed a blunted ventilatory response to hypoxia and no increase in P_0.1 . A dose-response relationship existed between the number of cigarettes smoked by the mother (0, 1 to 10, >10 per day) and the results for P_0.1 and tPTEF. Paternal smoking had no influence on the infant’s resting ventilation, respiratory drive, or ventilatory response to hypoxia. Conclusions: Infants born to smoking mothers have a reduced drive to breathe and a blunted ventilatory response to hypoxia. These findings may contribute to the increased risk of sudden infant death syndrome in these infants. (J Pediatr 1999;135:226-32)