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Cadmium (Cd) is a common additive in polyvinyl chloride (PVC) and polypropylene (PP) plastics. Aquatic organisms were inevitably co-exposed to PVC/PP microplastics (MPs) and Cd, but their combined toxicity is still unknown. In this study, adult zebrafish were exposed to 200 µg/L MPs (PVC or PP) and 10 µg/L Cd alone or in combination for 28 days to investigate their toxicity and mechanisms. Results showed that combined exposure with PVC/PP enhanced the Cd accumulation in the zebrafish intestine. Subsequently, toxicology analyses showed that both PVC and PP possessed synergistic toxicity with Cd, manifested by the exfoliation and necrosis of intestinal epithelial cells, and increased levels of interleukin-1ß (IL-1ß), superoxide dismutase (SOD) and malondialdehyde (MDA). PP exhibited a stronger synergistic effect than PVC. Integration of non-targeted metabolomics and 16S rRNA gene sequencing revealed that combined exposure to PVC and Cd induced intestine toxicity mainly through bile acid (BA) biosynthesis, fructose (Fru) and mannose (Man) metabolism, and pentose phosphate pathway (PPP). The combined exposure of PP and Cd induced toxicity through the arginine (Arg) and glutathione (GSH) metabolisms. Meanwhile, combined exposure of PVC/PP and Cd increased the abundance of intestinal Proteobacteria and pathogen Vibrio, and decreased the abundance of Gemmobacter. These changes indrectly promoted the synergistic toxicity of PVC/PP and Cd through metabolites, such as indole-3-pyruvate (IPyA), chenodeoxycholic acid (CDCA), and cholic acid (CA). These findings highlighted that more attention should be paid to the toxicity of chemicals at environmentally relevant concentrations, particularly those co-existing with MPs.

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The emergence of polystyrene (PS) nano- and microplastics (NMPs) and triclosan (TCS) as environmental contaminants has raised concerns about their combined toxicities to organisms, but the complex toxicity arising from their interactions and the underlying molecular mechanisms remain obscure to us. In this study, we comprehensively detected the combined toxicity of PS-NMPs and TCS via the dose-dependent yeast functional genomics profiling. Firstly, our findings demonstrated that the combined exposure to PS-NMPs and TCS elicited a synergistic toxic effect in which the toxicity depended on the size of the PS-NMPs. Secondly, we found that TCS exposure, either alone or in combination with PS-NMPs, influenced lipid biosynthetic processes and ATP export pathways, while the unique responsive genes triggered by combined exposure to TCS and PS-NMPs are significantly enriched in mitochondrial translation, ribosomal small subunit assembly, and tRNA wobble uridine modification. Thirdly, our results demonstrated that point of departure (POD) at the pathway level was positively correlated with IC50, and POD was a more sensitive predictor of toxicity than the apical toxicity endpoints. More importantly, our findings suggested that the combined exposure of PS-NMPs in a size-dependent manner not only alleviated the harmful effects of TCS on glycerophospholipid metabolism, but also exacerbated its negative impact on oxidative phosphorylation. Collectively, our study not only provides new insights into the intricate molecular mechanisms that control the combined toxicity of PS-NMPs and TCS, but also confirms the effectiveness of the dose-dependent functional genomics approach in elucidating the molecular mechanisms of the combined toxicity of pollutants.

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Pesticides are typically present as combinations within soil ecosystems and have detrimental effects on untamed surroundings. However, the collective impacts and fundamental mechanisms of pesticides on soil living beings are currently inadequately assessed. In our current work, we evaluated the interactive consequences of clothianidin (CLO) and prochloraz (PRO) on earthworms (Eisenia fetida) using several toxicological tests, such as acute adverse effects, biocatalytic activity, and alterations in transcriptional activity. The findings revealed that CLO (with a 14-day LC50 value of 6.08 mg kg-1) exhibited greater toxicity compared to PRO (with a 14-day LC50 value of 79.41 mg kg-1). Moreover, the combinations of CLO and PRO had synergistic acute effects on E. fetida. Additionally, the activities of POD, CAT, and GST were significantly varied in most instances of single and mixed treatments when compared to the control. Surprisingly, the transcriptional levels of four genes (gst, sod, crt, and ann), related to oxidative load, metabolic detoxification systems, endoplasmic reticulum, and oxytocin neuropeptide, respectively, were also altered in response to single and mixture exposures, as compared to the control. Alterations in enzyme activity and gene transcriptional level could serve as early indicators for detecting co-exposure to pesticides. The findings of this research offered valuable holistic understanding regarding the toxicity of pesticide combinations on earthworms. Further research should be conducted to investigate the persistent effects of pesticide mixtures on terrestrial invertebrates in order to draw definitive conclusions about the associated risks.

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In this study, microalgae Chlorella vulgaris (C. vulgaris) were simultaneously exposed to environmental concentrations of amino-functionalized polystyrene nanoplastics (PS-NH2; 0.05, 0.1, 0.2, 0.3 and 0.4 mg/L) and the world's second most used pesticide, the herbicide atrazine (ATZ; 10 µg/L), in the absence and presence of humic acid (HA; 1 mg/L) for 21 days. Due to the low concentrations of PS-NH2, the majority of them could not cause a significant difference in the end-points of biomass, chlorophylls a and b, total antioxidant, total protein, and superoxide dismutase and malondialdehyde compared to the control group (p > 0.05). On the other hand, by adding ATZ to the PS-NH2, all the mentioned end-point values showed a considerable difference from the control (p < 0.05). The exposure of PS-NH2+ATZ treatments to the HA could remarkably reduce their toxicity, additionally, HA was able to decrease the changes in the expression of genes related to oxidative stress (e.g., superoxide dismutase, glutathione reductase, and catalase) in the C. vulgaris in the most toxic treatment group (e.g., PS-NH2+ATZ). The synergistic toxicity of the PS-NH2+ATZ group could be due to their enhanced bioavailability for algal cells. Nevertheless, the toxicity alleviation in the PS-NH2+ATZ treatment group after the addition of HA could be due to the eco-corona formation, and changes in their zeta potential from positive to negative value, which would increase their electrostatic repulsion with the C. vulgaris cells, in such a way that HA also caused a decrease in the formation of C. vulgaris-NPs hetero-aggregates. This research underscores the complex interplay between PS-NH2, ATZ, and HA in aquatic environments and their collective impact on microalgal communities.

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While combinations of pesticides better represent actual conditions within aquatic ecosystems, the specific toxic effects of these combinations have not been determined yet. The objective of this research was to assess the combined impact of imazalil and azoxystrobin on the hook snout carp (Opsariichthys bidens) and delve into the underlying causes. Our findings indicated that the 4-day LC50 value for imazalil (1.85 mg L-1) was greater than that for azoxystrobin (0.90 mg L-1). When imazalil and azoxystrobin were combined, they presented a heightened effect on the species. Enzyme activities like SOD, CAT, GST, and CarE, along with androgen and estrogen levels, displayed marked differences in most single and combined treatments in comparison to the baseline group. Moreover, four genes (mn-sod, cu-sod, il-1, and esr) related to oxidative stress, immunity, and the endocrine system exhibited more pronounced expression changes when exposed to combined pesticides rather than individual ones. Our tests revealed that the combined use of imazalil and azoxystrobin had more detrimental effect on aquatic vertebrates than when evaluated individually. This finding suggested that future ecological hazard analyses based only on individual tests might not sufficiently safeguard our aquatic ecosystems.

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In recent years, nanoplastics (NPs) and triclosan (TCS, a pharmaceutical and personal care product) have emerged as environmental pollution issues, and their combined presence has raised widespread concern regarding potential risks to organisms. However, the combined toxicity and mechanisms of NPs and TCS remain unclear. In this study, we investigated the toxic effects of polystyrene NPs and TCS and their mechanisms on KGN cells, a human ovarian granulosa cell line. We exposed KGN cells to NPs (150 µg/mL) and TCS (15 µM) alone or together for 24 hours. Co-exposure significantly reduced cell viability. Compared with exposure to NPs or TCS alone, co-exposure increased reactive oxygen species (ROS) production. Interestingly, co-exposure to NPs and TCS produced synergistic effects. We examined the activity of superoxide dismutase (SOD) and catalase (CAT), two antioxidant enzymes; it was significantly decreased after co-exposure. We also noted an increase in the lipid oxidation product malondialdehyde (MDA) after co-exposure. Furthermore, co-exposure to NPs and TCS had a more detrimental effect on mitochondrial function than the individual treatments. Co-exposure activated the NRF2-KEAP1-HO-1 antioxidant stress pathway. Surprisingly, the expression of SESTRIN2, an antioxidant protein, was inhibited by co-exposure treatments. Co-exposure to NPs and TCS significantly increased the autophagy-related proteins LC3B-II and LC3B-Ⅰ and decreased P62. Moreover, co-exposure enhanced CASPASE-3 expression and inhibited the BCL-2/BAX ratio. In summary, our study revealed the synergistic toxic effects of NPs and TCS in vitro exposure. Our findings provide insight into the toxic mechanisms associated with co-exposure to NPs and TCS to KGN cells by inducing oxidative stress, activations of the NRF2-KEAP1-HO-1 pathway, autophagy, and apoptosis.

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Honey bees are unintentionally exposed to a wide range of chemicals through various routes in their natural environment, yet research on the cumulative effects of multi-chemical and sublethal exposures on important caste members, including the queen bee and brood, is still in its infancy. The hive's social structure and food-sharing (trophallaxis) practices are important aspects to consider when identifying primary and secondary exposure pathways for residential hive members and possible chemical reservoirs within the colony. Secondary exposures may also occur through chemical transfer (maternal offloading) to the brood and by contact through possible chemical diffusion from wax cells to all hive members. The lack of research on peer-to-peer exposures to contaminants and their metabolites may be in part due to the limitations in sensitive analytical techniques for monitoring chemical fate and dispersion. Combined application of automated honey bee monitoring and modern chemical trace analysis techniques could offer rapid progress in quantifying chemical transfer and accumulation within the hive environment and developing effective mitigation strategies for toxic chemical co-exposures. To enhance the understanding of chemical fate and toxicity within the entire colony, it is crucial to consider both the intricate interactions among hive members and the potential synergistic effects arising from combinations of chemical and their metabolites.

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The adsorption of toxic substances on polystyrene microplastics (PSMPs) can modify their biological toxicity and exacerbate the threat to human health. The effects of benzo [a] pyrene (B (a) P)-loaded aged PSMPs on colonic barrier integrity remains unclear. Here, we showed that binding environmentally relevant concentrations of B (a) P alteredl̥ the physicochemical features and markedly enhanced the toxicity of PSMPs. Compared to pristine PSMP, PSMP@B (a) P promoted colonic barrier degradation, body weight loss, colon length shortening, oxidative stress (OS), autophagy, inflammation, and bacterial translocation. Microplastic (MP) exposure induced injury to the colon barrier, including tight junction (TJ) and mucosal barriers, via overactivation of the Notch signalling pathway under increased OS in mice and intestinal organoids. Notably, PSMP@B (a) P exposure exacerbated damage to TJ and the mucosal barrier via the overproduction of reactive oxygen species (ROS), which could be related to the release of B (a) P from PSMP@B (a) P induced by the acidic environment of autophagosomes, which in turn exert synergistic toxic effects with PSMPs. Our study elucidates some of the potential molecular mechanisms by which B (a) P enhances PSMP-related intestinal toxicity, which provides a potential therapeutic approach for diseases caused by PSMP@B (a)P and PSMP pollution.

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The extensive use of pesticides has negative effects on the health of insect pollinators. Although pollinators in the field are seldom exposed to individual pesticides, few reports have assessed the toxic impacts of pesticide combinations on them. In this work, we purposed to reveal the combined impacts of tetrachlorantraniliprole (TET) and tebuconazole (TEB) on honey bees (Apis mellifera L.). Our data exhibited that TET had greater toxicity to A. mellifera (96-h LC50 value of 298.2 mg a.i. L-1) than TEB (96-h LC50 value of 1,841 mg a.i. L-1). The mixture of TET and TEB displayed acute synergistic toxicity to the pollinators. Meanwhile, the activities of CarE, CYP450, trypsin, and sucrase, as well as the expressions of five genes (ppo, abaecin, cat, CYP4G11, and CYP6AS14) associated with immune response, oxidative stress, and detoxification metabolism, were conspicuously altered when exposed to the mixture relative to the individual exposures. These results provided an overall comprehension of honey bees upon the challenge of sublethal toxicity between neonicotinoid insecticides and triazole fungicides and could be used to assess the intricate toxic mechanisms in honey bees when exposed to pesticide mixtures. Additionally, these results might guide pesticide regulation strategies to enhance the honey bee populations.

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Tris (2-chloroethyl) phosphate (TCEP) is a newly developed organophosphorus flame retardant that has been increasingly detected in soil as a contaminant. Nanoremediation is a potential solution for the control of TCEP, while the effectiveness and ecological risks are poorly understood. Here, we investigated the physicochemical interactions and joint toxicity of nano zero-valent iron (nZVI) (50-5000 mg/kg) and TCEP (50-5000 µg/kg) at environmental relevant concentrations to earthworms (Eisenia fetida) in soil. During a 28-d exposure, TCEP in soil was neither self-degraded nor removed by nZVI, and the individual toxicity of TCEP on the physiology of earthworms was significantly higher than that of nZVI. Notably, nZVI was found to synergize the toxicity of TCEP to earthworms without showing the classical "Trojan horse effect". Mechanically, TCEP mainly induced a typical neurotoxicity, and indirectly inhibited the food ingestion and growth performance of earthworms; nZVI induced iron poisoning aggravated the intestinal damage and directly inhibited the energy metabolism, therefore exacerbated the TCEP-induced malnutrition. Our findings provide new insights into the toxic mechanisms of nZVI-TCEP co-exposure to soil organisms, and emphasize the necessity of risk assessment and cautious usage of nanoremediation in newly emerged contaminations.

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Di-(2-ethylhexyl) phthalate (DEHP) is a dominant phthalic acid ester in the environment and commonly occurs at high concentration in agricultural soils. Its influence on the soil microbial community has been widely reported, while research related to its effects on microbial structure, function, and interactions in the rhizosphere, a microbial hotspot region in the terrestrial ecosystem, is still limited. This study investigated the response of microbes in the rhizosphere to DEHP contamination. DEHP reduced microbial quantity, shifted the microbial community structure, and enriched the soil bacteria with potential DEHP degraders. Although the rhizosphere can alleviate DEHP toxicity, DEHP still played an important role in microbial community construction in the rhizosphere. Interestingly, some microbes were influenced by the synergistic toxicity effect of DEHP addition and plant growth, and there were significant differences in their relative abundance and alpha diversity in soil treated with both DEHP and planting compared to soils with just DEHP spiking or planting. The genes related to cell motility, metabolism of terpenoids and polyketides, protein families, genetic information processing, and replication and repair pathways changed only in soil treated with both DEHP and planting further proved the existence of synergistic toxicity. Anyway, the impact of DEHP on microbial function in the rhizosphere was important with 52.42‰ of the genes being changed. The change in cell motility, biofilm formation, and genes related to the quorum sensing pathway might affect the relationship between microbes, which play a crucial role in ecosystem function. This was further proven by changes in the microbial co-occurrence pattern. Our results can benefit risk evaluation of DEHP to microbial community in the rhizosphere, which is important for the effective function of terrestrial ecosystems and soil health.

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Hazardous chemicals are commonly found in cereals and cereal-based products. However, most studies focus on the individual effects of these mycotoxins or metals, rather than their combined toxicity. The main objective of this study was to evaluate the combined effects of cadmium (Cd) and ochratoxin A (OTA) on intestinal barrier integrity using Caco-2 cells and pig small intestinal epithelial (PSI) cells as models of intestinal epithelial cells and to measure alterations in cell survival and barrier integrity. The combined effects on cell viability were assessed in terms of a combination of index values. These findings showed that co-exposure to Cd + OTA had synergistic effects on Caco-2 and PSI cells at 25%, 50%, and 75% inhibitory concentrations (IC25, IC50, and IC75, respectively) against cell viability. Individual Cd and OTA treatments had no effect, but combined Cd + OTA exposure resulted in synergistic down-regulation of paracellular apical junction complex proteins, such as claudin-1, occludin, and E-cadherin. The current findings indicate that the combined effects of OTA + Cd may have consequences at the gut level, which should not be underestimated when considering their risk to human health.

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Little attention has been paid to the problem of the combined toxicity of accumulated antibiotics on humans from food and clinical treatments. Therefore, we used human hepatocytes to study the joint toxicity of four common antibiotics. The cytotoxicity of enrofloxacin (ENR), combined with ciprofloxacin (CFX), florfenicol (FFC), or sulfadimidine (SMD) on THLE-2 cells was determined by CCK-8 assays; then their joint toxicity was evaluated using CalcuSyn 2.0. Dose-effect curves and median-effect plots established on large amounts of data and CI values were calculated to judge the nature of the combination's interaction. ED50, ED75, and ED90 were predicted to elucidate the changing trend of the concentration on the toxicity of each drug pair. The ENR-CFX and ENR-FFC pairs exhibited synergistic toxicity only at special concentration rates, while ENR and SMD synergistically induced cytotoxicity at almost all the concentration rates studied. The mixed ratio was a significant factor for synergistic toxicity and should be evaluated in all combined effect studies. These results suggested that the combined toxicity of these four drugs should be taken into account in their risk assessment.

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Camel milk has been considered as an important source of nutrients and is commercialized in many countries of the world including the Middle East. This study aimed to investigate the presence of mycotoxins in camel feed and milk samples in comparison with the cow milk. Fumonisins (FUM), ochratoxin A (OTA), and zearalenone (ZEN) were detected in 14%, 39%, and 39% of the tested camel feed samples, respectively. Among the tested camel feed samples, 8.3% and 5.6% were co-contaminated with OTA+FUM and FUM+ZEN, respectively. In the case of milk samples, 46.15% of camel and 63.63% of cow were found contaminated with aflatoxin M1 (AFM1). In total, 16.2% and 8.1% of the milk samples were simultaneously contaminated with two and three mycotoxins, respectively. Although the levels of individual mycotoxins in the camel feed and milk samples were within the European Union (EU) permissible limits, their co-occurrence may pose severe risk to human and animal health due to possible additive and/or synergistic toxicities.

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Mycotoxins can impart different types of combined toxicity to humans and animals, therefore, it is critical to understand the underlying mechanisms to eliminate the harm. Herein a combination of zearalenone (ZEA) at 2 µM and deoxynivalenol (DON) at 0.1 µM decreased cell viability and increased ROS level in HepG2 cells, suggesting synergistic toxicity exerted by ZEA and DON even at their low toxic concentrations. Moreover, apoptosis and inflammatory response were promoted after the co-exposure of ZEA and DON, indicated by the increased expression of BAX, Caspase-3, IL-1ß and IL-6 genes. Such synergistic toxicity was closely associated with miR-221-mediated PTEN/PI3K/AKT signal pathway, with a negative regulatory relationship between PTEN and PI3K/AKT signaling. MiR-221 could influence cell viability and ROS level to counter the combined toxicity of ZEA and DON through targeting directly PTEN gene. This study demonstrated the toxicological impact of mycotoxin interactions on cells, and critical role of the interplay between miRNAs and PTEN in monitoring the synergistic toxicity of mycotoxin mixture.

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Identification of the maximum tolerated dose combination (MTDC) of cancer drugs is an important objective in phase I oncology trials. Numerous dose-finding designs for drug combination have been proposed over the years. Copula-type models exhibit distinctive advantages in this task over other models used in existing competitive designs. For example, their application enables the consideration of dose-limiting toxicities attributable to one of two agents. However, if a particular combination therapy demonstrates extremely synergistic toxicity, copula-type models are liable to induce biases in toxicity probability estimators due to the associated Fréchet-Hoeffding bounds. Consequently, the dose-finding performance may be worse than those of other competitive designs. The objective of this study is to improve the performance of dose-finding designs based on copula-type models while maintaining their advantageous properties. We propose an extension of the parameter space of the interaction term in copula-type models. This releases the Fréchet-Hoeffding bounds, making the estimation of toxicity probabilities more flexible. Numerical examples in various scenarios demonstrate that the performance (e.g., the percentage of correct MTDC selection) of the proposed method is better than those exhibited by existing copula-type models and comparable with those of other competitive designs, irrespective of the existence of extreme synergistic toxicity. The results obtained in this study could motivate the real-world application of the proposed method in cases requiring the utilization of the properties of copula-type models.

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Anabaenopeptins and microcystins are oligopeptides produced by bloom-forming cyanobacteria. We determined in vivo effects of anabaenopeptin-B (AN-B) and two variants of microcystins of different hydrophobicity (MC-LR and MC-LF) on the physiology of Daphnia magna. Heart rate, thoracic limb activity and post-abdominal claw activity were determined by digital video analysis and oxygen consumption by Oxygraph + system. EC50 calculation and isobole methodology for interactive effects of AN-B and MC-LR mixture were used. Daphnids' responses to all three oligopeptides were concentration- and time-dependent. MC-LF was the most potent inhibitor of heart rate, thoracic limb activity, post-abdominal claw activity and oxygen consumption. AN-B was more toxic than MC-LR toward oxygen consumption; it inhibited the movements of limbs and post-abdominal claw similarly to MC-LR, but did not inhibit heart rate. The strongest toxic effects were induced by the binary mixture of AN-B with MC-LR at the sum concentration equal to the concentration of the single compounds. First time direct synergistic toxic effects of the cyanopeptides on all the physiological parameters were found. The obtained results explain stronger disturbances in aquatic organisms caused by cyanobacterial cell contents than the individual cyanopeptides present even at higher concentrations. Other metabolites and their interactions need further studies.

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Anaerobic fermentation is crucial to resource utilization of waste activated sludge (WAS). However, accumulated microplastics (MPs) in sludge could not be ignored. Here, a typical MP, polystyrene (PS), was selected to study the effects of different concentrations of PS on anaerobic fermentation under the optimal volatile fatty acids (VFAs) production. Compared to the control, low PS concentrations (30 particles/g total solid) significantly (p = 0.002) increased the production of VFAs to 112.8 ± 2.4% due to solubilization enhancement and enzymatic activity. High concentrations of PS (90 particles/g total solid) significantly (p = 0.000) decreased VFAs production to 83.01 ± 0.76% because of the inactive related microbial activities, although organic matter release was enhanced in the initial stage. Mechanism studies showed that the toxicity of high PS concentration could be attributed to reactive oxygen species (ROS) production, excess sodium dodecyl sulfate (SDS), and synergistic toxicity of aged MPs with external pollutants.

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Silver nanoparticles (AgNPs) are one of the most commonly used nanomaterials in industrial and agricultural production. Glyphosate is a broad-spectrum systemic herbicide, which mainly acts in the phloem of weeds that compete with crop growth and is widely used in agriculture. This study investigated the interactive effects of AgNPs and glyphosate on the physiological morphology, gene transcription, and rhizosphere microorganisms of wheat. Our results demonstrated that wheat growth, and the structure and diversity of rhizosphere microorganisms were slightly influenced by AgNPs and glyphosate single treatment at the test concentration. However, AgNPs and glyphosate (Gly) combined treatment (AgNPs + Gly) strongly inhibited wheat growth and influenced gene transcription. In total, 955, 601, and 1336 genes were determined to be differentially expressed in AgNPs, glyphosate, and combined treatment, respectively. According to KEGG analysis, the combined groups induced an antioxidant response by upregulating the transcription of phenylpropanoid biosynthesis-related genes. In addition, more energy was needed, and disrupted cell membrane was shown in the combined treatment, which displayed in the upregulation of sucrose, starch, and lipid synthesis. Moreover, the relative abundance of Bradyrhizobium, Devosia, Kribbella, Sphingopyxis (nitrogen-fixing bacteria), and Streptomyces (plant growth-promoting bacteria) in soil microbiota were decreased, implicated that nitrogen fixation and some beneficial substance secretions were inhibited by the combined treatment. This study emphasized that the synergetic effects of AgNPs and glyphosate exerted a negative impact on wheat growth.

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Although there is considerable evidence that a subset of infants has an increased risk of sudden death after receiving vaccines, health authorities eliminated "prophylactic vaccination" as an official cause of death, so medical examiners are compelled to misclassify and conceal vaccine-related fatalities under alternate cause-of-death classifications. In this paper, the Vaccine Adverse Event Reporting System (VAERS) database was analyzed to ascertain the onset interval of infant deaths post-vaccination. Of 2605 infant deaths reported to VAERS from 1990 through 2019, 58 % clustered within 3 days post-vaccination and 78.3 % occurred within 7 days post-vaccination, confirming that infant deaths tend to occur in temporal proximity to vaccine administration. The excess of deaths during these early post-vaccination periods was statistically significant (p < 0.00001). A review of the medical literature substantiates a link between vaccines and sudden unexplained infant deaths. Several theories regarding the pathogenic mechanism behind these fatal events have been proposed, including the role of inflammatory cytokines as neuromodulators in the infant medulla preceding an abnormal response to the accumulation of carbon dioxide; fatal disorganization of respiratory control induced by adjuvants that cross the blood-brain barrier; and biochemical or synergistic toxicity due to multiple vaccines administered concurrently. While the findings in this paper are not proof of an association between infant vaccines and infant deaths, they are highly suggestive of a causal relationship.