Safety assessment of EPA-rich triglyceride oil produced from yeast: genotoxicity and 28-day oral toxicity in rats.

The 28-day repeat-dose oral and genetic toxicity of eicosapentaenoic acid triglyceride oil (EPA oil) produced from genetically modified Yarrowia lipolytica yeast were assessed. Groups of rats received 0 (olive oil), 940, 1880, or 2820 mg EPA oil/kg/day, or fish oil (sardine/anchovy source) by oral gavage. Lower total serum cholesterol was seen in all EPA and fish oil groups. Liver weights were increased in the medium and high-dose EPA (male only), and fish oil groups but were considered non-adverse physiologically adaptive responses. Increased thyroid follicular cell hypertrophy was observed in male high-dose EPA and fish oil groups, and was considered to be an adaptive response to high levels of polyunsaturated fatty acids. No adverse test substance-related effects were observed on body weight, nutritional, or other clinical or anatomic pathology parameters. The oil was not mutagenic in the in vitro Ames or mouse lymphoma assay, and was not clastogenic in the in vivo mouse micronucleus test. In conclusion, exposure for 28 days to EPA oil derived from yeast did not produce adverse effects at doses up to 2820 mg/kg/day and was not genotoxic. The safety profile of the EPA oil in these tests was comparable to a commercial fish oil.

Female resistance to hypoxia: does it explain the sex difference in mortality rates?

There is currently no accepted explanation in the medical literature for the lower female total mortality rate in infancy, childhood and adulthood. We review the pediatric mortality data provided by Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO) and show that for causes of respiratory infant death that are apparently independent of gender (e.g., suffocation from inhalation of food or other object), there is a consistently one-third lower rate of mortality in the female than in the male. This one-third lower mortality for causes of death with a respiratory terminal event is hypothesized to be due to an X-linked dominant allele that occurs with frequency 1/3. It appears as if a second X chromosome provides the one-third extra probability of protection afforded for an XX female compared with an XY male. It is suggested that the allele's function is unmasked during transient periods of cerebral anoxia, requiring a mechanism for anaerobic oxidation to prevent the death of respiratory control neurons in the brain stem. Examples of the female one-third extra chance of resistance to hypoxia are given for causes of death in infancy, such as infant respiratory distress syndrome (IRDS) and sudden infant death syndrome (SIDS), and for causes of suffocation in childhood and asphyxiation in adulthood. DNA testing of the X chromosome of probands from causes of respiratory death, such as SIDS and IRDS, where there is a one-third lower female than male death rate, is a future direction that can verify the existence of the proposed allele.

The X-linkage hypotheses for SIDS and the male excess in infant mortality.

Sudden Infant Death Syndrome is characterized globally by a 50% excess in males per 1000 live births of each gender. We previously hypothesized that this male excess may arise from a single X-linked gene locus with a dominant allele (p = 1/3) that is protective against potentially terminal cerebral anoxia by catalyzing anaerobic oxidation and a recessive allele (q = 2/3) that is unprotective. We now hypothesize this same terminal mechanism for all other causes of infant respiratory death (50% male excess) and that infant cardiac death is equally probable for males and females (0% male excess). With these hypotheses, we model the male excess of all infant mortality (under 5 years) as 25% per 1000 live births of each gender. We show for the USA (1979-2000) that this model of a 25% male excess accurately predicts the male excess mortality under 1 year (24.15%), from 1 to 4 years (25.42%), and under 5 years (24.51%).

A Unifying Theory for SIDS.

The Sudden Infant Death Syndrome (SIDS) has four distinctive characteristics that must be explained by any theory proposed for it. (1) A characteristic male fraction of approximately 0.61 for all postneonatal SIDS in the US; (2) a distinctive lognormal-type age distribution arising from zero at birth, mode at about 2 months, median at about 3 months, and an exponential decrease with age going towards zero beyond one year; (3) a marked decrease in SIDS rate from the discovery that changing the recommended infant sleep position from prone to supine reduced the rate of SIDS, but it did not change the form of the age or gender distributions cited above; (4) a seasonal variation, maximal in winter and minimal in summer, that implies subsets of SIDS displaying evidence of seasonal low-grade respiratory infection and nonseasonal neurological prematurity. A quadruple-risk model is presented that fits these conditions but requires confirmatory testing by finding a dominant X-linked allele protective against cerebral anoxia that is missing in SIDS.

Genotoxicity of radiofrequency signals. I. Investigation of DNA damage and micronuclei induction in cultured human blood cells.

As part of a comprehensive investigation of the potential genotoxicity of radiofrequency (RF) signals emitted by cellular telephones, in vitro studies evaluated the induction of DNA and chromosomal damage in human blood leukocytes and lymphocytes, respectively. The signals were voice modulated 837 MHz produced by an analog signal generator or by a time division multiple access (TDMA) cellular telephone, 837 MHz generated by a code division multiple access (CDMA) cellular telephone (not voice modulated), and voice modulated 1909.8 MHz generated by a global system of mobile communication (GSM)-type personal communication systems (PCS) cellular telephone. DNA damage (strand breaks/alkali labile sites) was assessed in leukocytes using the alkaline (pH>13) single cell gel electrophoresis (SCG) assay. Chromosomal damage was evaluated in lymphocytes mitogenically stimulated to divide postexposure using the cytochalasin B-binucleate cell micronucleus assay. Cells were exposed at 37+/-1 degrees C, for 3 or 24 h at average specific absorption rates (SARs) of 1.0-10.0 W/kg. Exposure for either 3 or 24 h did not induce a significant increase in DNA damage in leukocytes, nor did exposure for 3 h induce a significant increase in micronucleated cells among lymphocytes. However, exposure to each of the four RF signal technologies for 24 h at an average SAR of 5.0 or 10.0 W/kg resulted in a significant and reproducible increase in the frequency of micronucleated lymphocytes. The magnitude of the response (approximately four fold) was independent of the technology, the presence or absence of voice modulation, and the frequency (837 vs. 1909.8 MHz). This research demonstrates that, under extended exposure conditions, RF signals at an average SAR of at least 5.0 W/kg are capable of inducing chromosomal damage in human lymphocytes.

In vivo mutagenicity and mutation spectrum in the bone marrow and testes of B6C3F1 lacI transgenic mice following inhalation exposure to ethylene oxide.

The lacI mutant frequency and mutation spectrum were determined in the bone marrow and testes of B6C3F1 lacI transgenic mice exposed by inhalation to ethylene oxide (EO). Groups of male transgenic lacI B6C3F1 mice were exposed to 0, 25, 50, 100 or 200 p.p.m. EO for up to 48 weeks (6 h/day, 5 days/week) and were killed at 12, 24 or 48 weeks of EO exposure for determination of lacI mutant frequency. In the bone marrow, the lacI mutant frequency was significantly increased at the two highest exposure levels (100 and 200 p.p.m.) and at the 48 week exposure time point. The shape of the exposure-response curve for lacI mutant frequency in the bone marrow was non-linear. DNA sequence analysis of the bone marrow mutation spectrum revealed that only AT-->TA transversions occurred at an increased frequency in EO-exposed mice: 25.4% in EO-exposed mice for 48 weeks (200 p.p.m.) compared with 1.4% in air controls. In testes, the lacI mutant frequency was increased at a single exposure level of 200 p.p.m. for 24 weeks. At 48 weeks, the lacI mutant frequency in testes was significantly increased to an equal degree at 25, 50 and 100 p.p.m. EO but not at 200 p.p.m. Analysis of the testes mutation spectrum in air control mice and in mice exposed to 200 p.p.m. EO for 48 weeks revealed that no single mutational type occurred at an increased frequency. In the testes, there was a small increase across all mutational types that was sufficient to increase the overall lacI mutation frequency although not significant individually. The mutation spectrum in testes of EO-exposed mice also revealed that the increased lacI mutant frequency observed at 25 or 50 p.p.m. EO was not due to an increase in mutant siblings (clonality). These data demonstrate that inhalation exposure to EO for up to 48 weeks produces distinct mutagenic responses in bone marrow and testes.