and botanical research relevant to the conservation, sustainable use and management of australian plants will be undertaken. - the gardens will provide a national focus for, and national and international leadership in, the conservation of plant biodiversity. in particular, it will : - contribute to a national database of rare or threatened australian plants ; - cooperate with other conservation - oriented groups in species recovery - provide support for a network of australian regional botanic gardens and kindred institutions to promote conservation and sustainable use of australian - develop an ex situ collection of plants and seed of rare or threatened taxa for use in recovery plans and interpretive and educational programs, and as a gene bank. - biodiversity conservation and environmental sustainability will be strong underlying messages in education programs, indoor exhibitions and interpreted planting themes. threatened plants will be grown and interpreted in prominent places within the gardens and their status will be indicated where appropriate. - the gardens will support the australian network for plant conservation and continue its involvement with botanic gardens conservation international. it will cooperate with kindred organisations in staff exchange activities related to conservation. - the gardens and the cpbr will work closely with other government agencies on programs promoting vegetation and landscape conservation, threatened species conservation, and the protection of natural ecosystems from invasive weeds, both on and off reserves. - the gardens and the cpbr will contribute to the ongoing development of a national threatened species database, and document threatened plants in the herbarium, the living collections and the photograph collections. - the gardens will collect and maintain genetically significant living stocks of threatened species including variants, particularly those of the local region, and collaborate with other institutions in developing a national endangered - development of horticultural protocols for conservation purposes will focus on propagation and seed storage. - there will be maintenance and further development of the seed bank as a repository for rare or threatened species. - propagation material of rare or threatened plants will be made available to regional botanic gardens and kindred organisations with a conservation - regional botanic gardens and kindred institutions will be encouraged to raise awareness of conservation issues with the loan of relevant display material and educational resources developed at the gardens. 15 december, 2004, webmaster, anbg ( firstname. lastname @ example. org )


given by new mexico in 2005 u. s. capitol visitor center this statue of po ’ pay was given to the national statuary hall collection by new mexico in 2005. po ’ pay was born around 1630 in the san juan pueblo, in what is now the state of new mexico ; his given name, popyn, means " ripe squash " in the tewa language. as an adult he became a religious leader and was responsible for healing as well as for his people ’ s spiritual life. he also knew of his people ’ s suffering under spanish settlers, who forced them to provide labor and food to support the spanish community. the spaniards also pressured them to give up their religion and way of life and to adopt christianity — those found practicing their religion were tortured and sometimes executed. in 1675 po ’ pay and 46 other pueblo leaders were convicted of sorcery ; he was among those flogged, while others were executed. in 1680 po ’ pay organized the pueblo revolt against the spanish. according to legend, to coordinate the timing of the uprising, he and his followers sent runners to each pueblo with knotted deerskin strips. one knot was to be untied each day, and the revolt would begin on the day the last one was untied. however, the spaniards arrested two of the runners, and the pueblos were quickly notified to accelerate the revolt. the attacks began on august 10, two days before the last knot would have been untied. the spaniards took refuge at santa fe ; the besieging indians cut off their water supply but soon permitted them to leave the area. the pueblo revolt helped to ensure the survival of the pueblo culture and shaped the history of the american southwest. in 1997, the new mexico legislature selected po ’ pay as the subject of the state ’ s second statue for the national statuary hall collection and created the new mexico statuary hall commission, whose members were appointed by governor gary johnson. four sculptors were selected to create maquettes, and cliff fragua was awarded the commission in december 1999. it will be the seventh statue of a native american in the collection ; the others are king kamehameha i, will rogers ( who had cherokee ancestors ), sakakawea, sequoyah, washakie, and sarah winnemucca. the seven - foot - high statue was carved from pink tennessee marble ( making it the only colored marble statue in the collection ) and stands on a three - foot - high pedestal comprised of a steel frame clad in black granite.


winnemucca. the seven - foot - high statue was carved from pink tennessee marble ( making it the only colored marble statue in the collection ) and stands on a three - foot - high pedestal comprised of a steel frame clad in black granite. its acceptance marked the first time at which every state in the union has been represented by two statues in the collection. in addition, po ’ pay is historically the first person represented in the collection to be born on what would become american soil. no image or written description of po ’ pay is known to exist. sculptor cliff fragua describes the statue thus : in my rendition, he holds in his hands items that will determine the future existence of the pueblo people. the knotted cord in his left hand was used to determine when the revolt would begin. as to how many knots were used is debatable, but i feel that it must have taken many days to plan and notify most of the pueblos. the bear fetish in his right hand symbolizes the center of the pueblo world, the pueblo religion. the pot behind him symbolizes the pueblo culture, and the deerskin he wears is a humble symbol of his status as a provider. the necklace that he wears is a constant reminder of where life began, and his clothing consists of a loin cloth and moccasins in pueblo fashion. his hair is cut in pueblo tradition and bound in a chongo. on his back are the scars that remain from the whipping he received for his participation and faith in the pueblo ceremonies and religion. fragua, an indian from jemez pueblo, studied sculpture in italy, california, and new mexico ; he created his first stone sculpture in 1974.


when the kids at notlabs first got their hands on a makerbot replicator, the ingenious 3d printer that can make just about anything you want, they quickly got down to business – making lego and kinex connectors, that is. as inconsequential as their decision may seem, it got us thinking : today, building blocks, but tomorrow? buildings themselves. the future isn ’ t as far as you may think. in the next two articles, i ’ ll introduce you to three visionaries who are already applying 3d printing technology to revolutionary effect : an engineer hoping to improve the human condition, a robotics expert with the goal of completing the sagrada familia ( or at least putting a structure on the moon ), and an architect at mit using nature - inspired materials to turn the design world on its head. if these three examples are anything to go by, 3d printing will revolutionize the world as we know it. but it begs the question : at what price? will it offer architects the freedom to design without the pesky limitations of built reality? or, like the scribes made redundant by gutenberg ’ s printing press, will 3d printing make the architect go extinct? the future potential to build and realize the concepts of the human mind lie just there, within the potential of the human mind. for years the architectural world has been struggling to keep up with the ability of pen - to - paper and the recent advents in nurb surface computer modeling, algorithmic and parametric architecture. this in - return has led to the building and technology industry playing catch - up with the recent advances in 3d architectural visualizations. in fact, as computer - aided design invaded these practices in the 1980s, radically transforming their generative foundations and productive capacities, architecture found itself most out - of - step and least alert, immersed in ideological and tautological debates and adrift in a realm of referents severed from material production.


“ the town that aluminum built ; ” “ the aluminum capital of the world ; ” “ the definitive company town in its heyday : ” these all describe the central arkansas community of bauxite. according to ernie deane ’ s “ arkansas place names, ” the pittsburg reduction company is credited as founder of the town named for the famous ore in 1907, though the general bauxite company had opened a mine and plant a few years earlier in 1897. the mining industry is gone today but the town remains a thriving community. at the peak of mining, bauxite had more than 7, 000 residents who lived and worked there. most of the company town no longer exists except for the community center. today the community center houses the bauxite museum, dedicated to the history of the town and the industry that built it. displays at the museum cover three decades, from the 1920s through the 1950s, and deal with such topics as family / community, the mining industry, the area ’ s ethnic diversity, military heritage, school days and sports. one of the most unusual and popular exhibits is what is known as " bauxite teeth, " a problem that affected both workers and residents in the early days of mining. though the local water stained teeth an unpleasant brown, doctors found the “ bauxite teeth ” to have harder enamel and be healthier than normal. other ways bauxite honors its heritage is the naming of the high school athletic teams – “ the miners ” - - while two main thoroughfares are named alcoa and reynolds after the major aluminum producers who mined there during the prime days of the industry. the ore also serves as the official state rock which is hard enough to have been used in various types of construction. it was used in 1887 to surface the road from sweet home to little rock. and in 1893 residents of the next - door - neighbor town of benton used the then unknown substance to build a home for dr. gann in lieu of payment for bills. the solid structure still stands and houses the gann museum of saline county.


tuesday 18 june laughing gull ( larus atricilla ) laughing gull fact file - find out more - print factsheet laughing gull description the laughing gull ( larus atricilla ) is a familiar bird of north american coasts with a distinctive appearance and almost hysterical laughing - like call ( 3 ). a small, black - hooded gull, this species has a grey back and grey wings, as well as a white breast and tail, a dark red bill and reddish - black legs. during the breeding season, the laughing gull has a distinctive black cap with narrow white crescents around the eyes, and will often have a suffusion of pink on the normally white breast. at other times of the year, the cap is lost and the head turns white, except for a residual dark patch behind the eye ( 4 ). before reaching maturity, juvenile laughing gulls undergo several moults, with plumage changing from light brown, with pale edged feathers and black primaries and secondaries, to having a whiter head, a grey back and a dusky breast ( 2 ) ( 4 ) ( 5 ). - leucophaeus atricilla. - goeland atricille. top - to keep eggs warm so that development is possible. - animals with no backbone. - in birds, the main flight feathers projecting along the outer edge of the wing. - in birds, the shorter flight feathers projecting along the inner edge of the wing. - an area occupied and defended by an animal, a pair of animals or a colony. iucn red list ( september, 2010 ) - del hoyo, j., elliott, a. and sargatal, j. ( 1996 ) handbook of the birds of the world. volume 3 : hoatzin to auks. lynx edicions, barcelona. the cornell lab of ornithology : all about birds - laughing gull ( september, 2010 ) burger, j. ( 1996 ) laughing gull ( larus atricilla ). in : poole, a. ( ed. ) the birds of north america online. cornell lab of ornithology, ithaca. available at : - perrins, c. ( 2009 ) the encyclopedia of birds. oxford university press, oxford, uk. - burger, j. ( 1996 ) a naturalist along the jersey shore. rutgers university press, new jersey, usa. birdlife international ( september, 2010 ) - view the contents of, and material on, the website ; - download and retain copies


- burger, j. ( 1996 ) a naturalist along the jersey shore. rutgers university press, new jersey, usa. birdlife international ( september, 2010 ) - view the contents of, and material on, the website ; - download and retain copies of the material on their personal systems in digital form in low resolution for their own personal use ; - teachers, lecturers and students may incorporate the material in their educational material ( including, but not limited to, their lesson plans, presentations, worksheets and projects ) in hard copy and digital format for use within a registered educational establishment, provided that the integrity of the material is maintained and that copyright ownership and authorship is appropriately acknowledged by the end user. laughing gull biology gulls in general are opportunistic feeders, and the laughing gull is no exception. it gathers at rubbish dumps to feed on scraps, follows tractors to catch disturbed insects and follows fishing boats to feed on discards. the laughing gull also pirates food from other bird species, including the brown pelican ( pelecanus occidentalis ), from which the laughing gull steals from its food pouch. in delaware, the horseshoe crab ( limulus polyphemus ) breeding season provides a plentiful supply of food for the laughing gull, as it feeds on the abundant eggs ( 2 ). breeding from late april in the southern colonies and from late may in the northern colonies, the laughing gull arrives at its breeding sites around a month before breeding to establish a territory and a nest site. upon arrival, the male laughing gull soon begins courting females with displays and offerings of fish, and this may last for up to two weeks. this courtship strategy not only helps to establish a pair bond, also provides the females with additional energy for egg production. a nest is built on elevated ground to prevent the nest from being dragged to sea at high tide ( 4 ) ( 6 ). typically, three eggs are laid and incubated by both the male and female for up to 28 days. whilst one bird incubates the eggs, the other forages for food and returns every three to four hours. once the chicks have hatched, the adult birds alternate between guarding the young and foraging. the adults do not bring prey back whole, instead regurgitating the food for the chicks ( 4 ). top laughing gull range in the summer, the laughing gull breeds along the north - eastern coast of america, before migrating southwards to central america and the


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i read the book " alone in the universe " by john gribbin recently. he argues that the conditions that produced intelligent ( sort of ) life on earth are incredibly rare, so this explains the " fermi paradox " : if there are aliens out there, why don ' t we see them? ( assuming as seems reasonable, that we don ' t ). he gives a lot of plausible reasons for why the rareness of life. like, only a certain part of the milky way is a good home for life. our planet has a magnetic field that shields it from the solar wind - charged particles that stream out of the sun. continental drift may not be common, and it ' s crucial for regulating the concentration of carbon dioxide in the atmosphere, which is a kind of natural thermostat for earth. he thinks there were serendipitous mass extinctions of life forms that were unlikely to become intelligent, like the ediacarans. they were a weird kind of multicellular life that were around before the cambrian. strangely shaped things. and so on. some of it is very questionable to me. like, he thinks that land life is much more likely to become technological, and that the reasons are obvious. i ' m not sure what the obvious reasons are and i looked online and didn ' t find them. i wondered if part of the reason was that aquatic creatures would be less likely to develop hands, but then i found that octopi can manipulate objects with their tentacles. a lot of technology wouldn ' t work underwater, but being underwater would make some things easier, too. aquatic intelligent creatures might be very good at spatial thinking since they live in 3 dimensions. he mentions the idea of an advanced civilization putting self - replicating machines out into the universe that would colonize everything in time, and report back what they found to the home planet. so why aren ' t there self - replicating alien machines on earth, if there are alien civilizations? but i ' m not convinced that an advanced civilization would necessarily want to do this, or that it would be at all practical or feasible. he talks about a dinosaur called troodon, which lived right before a 6 - mile wide rock ( probably ) smashed into the earth, causing the end - cretaceous extinction. he says based on its brain size, troodon was about as smart as a small baboon. so the dinosaurs were on their way to evolving intelligence when they were wiped out. it would be interesting to speculate what an intelligent creature


. he says based on its brain size, troodon was about as smart as a small baboon. so the dinosaurs were on their way to evolving intelligence when they were wiped out. it would be interesting to speculate what an intelligent creature that troodon could have evolved into, would have been like. they might have been more warlike than us ( not a happy thought ) since they were carnivorous and we evolved as omnivores. carnivores generally seem to be rather aggressive towards others of the same species. there are obviously a lot of pitfalls with arguing that life is rare, based on lucky accidents that produced us. evolution is very creative, and examples of convergent evolution show how the same solution to a problem that life is faced with, are found over and over. why shouldn ' t intelligence be a solution that convergent evolution finds over and over, on different planets, even? and, different solutions to different problems posed by different circumstances, could be found by alien life, and the limitations of our imagination are no argument against this. to me, the slow speed of light compared to the size of the cosmos seems a good reason why we ' d be left alone by them. the milky way galaxy is about 100, 000 light years in diameter. one could perhaps make a good argument that other intelligent life would exist on a roughly similar time scale to us, so that 100, 000 years would look like a long time to them, too. if it ' s true that conscious life is very rare, then it returns the specialness to us that science took away so much, by discovering the hugeness of the universe, that the sun and stars don ' t revolve around us, etc. the wonderful nature of our world is partly explained by the fact that we are here to see its wonders - which is made possible by the enormous size of the universe. for me, thinking about this kind of spacey thing is a mind - refreshing relief from the humdrum forced on me by health problems. and you can enjoy exploring the cosmos too in your imagination. in order to have technology - - anything from making a crude stone tool to building a space shuttle - - requires brains. brains require a constant supply of oxygen, which requires a heavly vascularized brain and a large heart, and large lungs to efficiently oxygenate the blood. fish are highly specialized and occupy a fairly restricted niche dependent on saline or fresh water, temperature, depth, etc,. they are streamlined swimmers with no ape


to get anywhere close to the dinos in the tropic and sub - tropic environments. i agree that that there is life - of one kind or another - on other planets, not just because of the large number of planets that have been discovered but because the nebulae in our galaxy, like the orion nebula, are producing an enormous amount of prebiotic molecules ( water, formaldehyde, cyanide sulfur dioxide and many more ). this has been going on long before the earth was formed, and it ' s inevitable that this raw material of life was here during the formation of the planet and was incorporated during its accretion period. for me, the question of where life came from, the earth or space, is moot. the earth is space stuff. so, the answer is yes to both questions. my conundrum is this : the dna / rna molecule is the " life " molecule for all living things on earth. if we expect to find earth - like life on other planets, it would have to have dna / rna. although i am convinced that this is the only molecule possible for life, i find it difficult to believe that it can be easily replicated. the other problem is the presence of the mitochondrion in all true cells. it is believed to have been a symbiotic bacterium which became incorporated into the cell and serves as a power house with its own genetic material, and has made it possible for more diversity. if ths process is not duplicated on other planets, what sort of life will we get then? these factors make me wonder whether life will be as prolific as we think, and that intelligence on par with ours will be very, very rare, much less superior to ours. to my knowledge, there is no self replicating molecule that exists other than dna / rna ; however, the pre - biotic chemistry for it exists. i assume the chemical precursors are pretty much consistent throughout the universe as is chemical reactivity. oxidation / reduction is the same here as well as in the most distant galaxy. as such, any rocky planet with a reducing atmosphere would be a potential life forming stage. there are, of course, many other factors necessary for successful life genesis and survival to the point of intelligence. intelligence may be rare but, imo, life is probably ubiquitous throughout the universe. jim, i can ' t quibble about what you ' ve said ( although i ' d like to ) but keep in mind that only one planet out of eight


intelligence may be rare but, imo, life is probably ubiquitous throughout the universe. jim, i can ' t quibble about what you ' ve said ( although i ' d like to ) but keep in mind that only one planet out of eight in our solar has has life on it. as to life on the other plants, and moons, it ' s pure speculation. he ' s not speaking of life on other planets within our solar system. none of the other planets in our solar system fit the necessary criteria for dna - based life. he ' s speaking of chemically - similar life on planets within similar orbits of other stars. there are a couple hundred billion stars within our galaxy alone. some of them must have suitable planets at orbits that are the appropriate distance to contain liquid water. thanks. the " goldilocks zone ". the point i was making was that the total number of planets is meaningless. additionally, mars may have had life, but no longer seems to, even though it has ice at the caps. might it have fallen into that zone? it ' s all a matter of degrees. the point i was making was that the total number of planets is meaningless. umm, no, it ' s not meaningless. when we ' re talking about a statistical likelihood of there being life on other planets, the planetary density of the galaxy and the universe is very much at issue. additionally, mars may have had life, but no longer seems to, even though it has ice at the caps. might it have fallen into that zone? it ' s all a matter of degrees. mars is a little outside of that zone. it is too far away from the sun for the energy from the sun to maintain its temperature within the necessary range for a long enough period of time. obviously, it passed through the necessary temperature range, at some point in its life - cycle, going from molten, after formation, to its current, relatively inert stage. there was quite possibly very simple life, at some point, but the window of time was too short for that life to evolve very much. mars might heat up significantly, after the sun goes into the red giant phase, in another 5 or 6 billion years, but that phase will be far too short of life to reform and evolve any amount worth speaking of. plus, mars and the outer plants might escape, during that period, in which case, it won ' t be warming, as it goes hurtling off into interstellar space. thanks. how do you determine the odds


any amount worth speaking of. plus, mars and the outer plants might escape, during that period, in which case, it won ' t be warming, as it goes hurtling off into interstellar space. thanks. how do you determine the odds of life being on any one planet? we do not have any sampling data. if your talking total mass of life, that ' s one thing, if you ' re talking odds, that ' s another. from our perspectve it ' s easy to determine that mars is not quite in the zone. how easy is it to ascertain from 20 lightyears distance. we have not explored the ice cap ( s ) on mars yet, neither have we drilled a deep core sample. on earth we have life forms living miles beneath the surface. so, there is much more to learn. how do i determine the odds of any given extrasolar - planet evolving life? i don ' t. i have no freaking clue. the only real statements that i can make are that there are a huge number of planets out there with life on them, because of the sheer numbers involved. i made a lot of approximations, based upon other people ' s numbers, to explain why i reject the fermi paradox, back on page one of this discussion. i can only make the most general sorts of conclusions, with my knowledge of the field. i agree with you that there must be abundant life out there, but i think fermi was speaking of life that was superior in intelligence and technology. on this point i agree with him that it probably doesn ' t exist. if life is dna - based, then evolution would operate under the same principles as it does on earth. since we now live in societies in which survival is no longer a life - and - death struggle, there is no selective pressure for us to get any smarter. the same would go for an alien life form. once they reached a comfortable, secure technological point there would be nothing requiring them to get larger brains than they have now. so, they would probably be just like us - - wondering why they haven ' t been visited by a technologically superior culture.... but i think fermi was speaking of life that was superior in intelligence and technology. he was speaking about intelligent species that have achieved interstellar travel, as we could possibly do, in another couple hundred years or so, if we don ' t wipe ourselves out, before then. on this point i agree with him that it probably doesn ' t


speaking about intelligent species that have achieved interstellar travel, as we could possibly do, in another couple hundred years or so, if we don ' t wipe ourselves out, before then. on this point i agree with him that it probably doesn ' t exist. if life is dna - based, then evolution would operate under the same principles as it does on earth. since we now live in societies in which survival is no longer a life - and - death struggle, there is no selective pressure for us to get any smarter. the same would go for an alien life form. what you ' re missing is that genetic evolution doesn ' t matter anymore ( or at least matters very little ), in our evolution as a species. our memetic evolution is what will eventually lead us to an interstellar culture or cause us to wipe ourselves out. also, he ' s not saying that other intelligent life doesn ' t exist in the galaxy. he ' s saying that if other intelligent life exists in the galaxy, the estimates ( such as the drake equation ) have problems. that ' s why it ' s a paradox. personally, i think most of the problems with the estimates have to do with underestimating the difficulties of interstellar travel and overestimating the effective age of the universe, in terms of how long interstellar civilizations would have been around, and how freely they would be able to move throughout the galaxy. part of the problem is that he assumes an effectively limitless time for colonial expansion, relative to the age of the universe. i don ' t think that the relative differences in time are quite as exponential as he assumes. i went through most of that back on page one. i think that at the more pessimistic end of the estimates, with the limitations of space travel factored in, it ' s not so hard to believe that we haven ' t had anyone probing us yet.


chapter 8 : health effects evaluation : in - depth analysis - ( section 8. 1 ) when to conduct an in - depth analysis - ( section 8. 2 ) tools and resources needed to support an in - depth analysis - ( section 8. 3 ) evaluating study ( ies ) on which exceeded health guidelines are based - ( section 8. 4 ) reviewing other dose - response data - ( section 8. 5 ) evaluating substance - specific factors that can increase or decrease the potential for harm - ( section 8. 6 ) evaluating site - specific health effects data - ( section 8. 7 ) presenting findings in the public health assessment document as part of the exposure evaluation ( described in chapters 5 and 6 ), you have identified who might come in contact with environmental contaminants, how those persons might be exposed, and the extent to which might be exposed ( over space and time ). as an initial step in the health effects evaluation ( described in chapter 7 ), you have compared, measured, or modeled exposure point concentrations to atsdr ' s media - specific comparison values. in some cases, you have estimated site - specific exposure doses and compared them to health guidelines. by now, you have clearly ruled out those pathways and substances that pose no health hazards, and you have retained those requiring more careful examination. this chapter provides guidance on how to perform the more in - depth analysis needed at sites where, during the exposure evaluation and screening analysis, health hazards have not been ruled out. to this point in the public health assessment processwith the exception of knowing the numeric value of the health - based comparison valueno information about the substance ( s ) of interest has been required. as depicted in figure 8 - 1, the process described in this chapter involves looking more closely at substance - specific information in the context of site exposures. the goal of this analysis is to provide perspective on what it means when a health - based screening value has been exceeded, and in some cases, how to address specific community health concerns regarding that situation. the analysis will help answer two important questions health assessors face : - are public health actions needed to prevent exposures? - are site - related exposures expected to cause harm? this chapter will guide you in evaluating and integrating exposure data ( i. e., site - specific exposure conditions that have been studied throughout the public health assessment process ) and substance - specific health effects data ( e. g., toxicologic, epidemiologic, and health outcome data ). the output of the


, site - specific exposure conditions that have been studied throughout the public health assessment process ) and substance - specific health effects data ( e. g., toxicologic, epidemiologic, and health outcome data ). the output of the analysis is a qualitative description of whether site exposure conditions are of sufficient nature, frequency, and magnitude to affect public health adversely. the outcome will also assist in determining an appropriate public health response. because of uncertainties regarding exposure conditions and the adverse effects associated with environmental levels of exposure, definitive answers on whether health effects actually will or will not occur are not always possible. however, providing a framework that puts site - specific exposures and the potential for harm in perspective is possible and is one of the primary goals of the public health assessment process. the narrative describing your findings should therefore lay out this framework. after discussing the criteria that will trigger an in - depth analysis ( section 8. 1 ) and the tools and resources available to support your analysis ( section 8. 2 ), this chapter will guide the health assessor through the following steps : - evaluating the experimental or human study ( ies ) on which the exceeded health guideline value was based. ( section 8. 3 ) - determining where site - specific dose estimates fall in relation to other dose - response data. ( section 8. 4 ) - reviewing other substance - specific factors that could increase or decrease the potential for harmful effects, such as our understanding of the overall behavior of the substance within the human body and the mechanism by which it exerts its toxic effect, knowledge of substance - specific effects among susceptible populations, and multiple chemical exposures. ( section 8. 5 ) - determining whether relevant site - specific health effects data should be evaluated in the public health assessment, such as mortality and morbidity data ( also called health outcome data ), or biologic monitoring data ( section 8. 6 ). - integrating relevant information and presenting it in the pha document. ( section 8. 7 ) not all public health assessments will require you to consider all the elements of the in - depth analysis described in this chapter. the level of analysis will differ across sites and will depend on the scope and complexity of site - related issues, such as the magnitude of exposures, the substance ( s ) under evaluation, and specific community health concerns. as you review and integrate exposure and health effects data, professional judgment is needed in weighing what is known and unknown, including uncertainties and data limitations. you may need assistance from other members


substance ( s ) under evaluation, and specific community health concerns. as you review and integrate exposure and health effects data, professional judgment is needed in weighing what is known and unknown, including uncertainties and data limitations. you may need assistance from other members of your site team or other technical specialists, including those with expertise in toxicology, epidemiology, medicine, and health physics. this chapter will guide you on how to work with these specialists to define the appropriate level of analysis for your site and in evaluating the strength and relevance of available information. as the health assessor, you will be responsible for integrating and communicating the findings of this analysis in the public health assessment document. 8. 1 when to conduct an in - depth analysis during the screening analysis ( chapter 7 ), after careful consideration of site - specific exposure conditions, you eliminated those substances and pathways not expected to result in adverse health effects. you then determined whether exposure to measured or modeled levels of contaminants required further evaluation. in many cases, you will not need to go any further. however, you should proceed with a more detailed analysis, as outlined in this chapter, if any of the following occur ( 1 ) : - site - specific exposure dose estimates exceed health - based guideline values ( e. g., mrls are exceeded or theoretical cancer risk levels exceed 10 - 6 ). - no relevant and reliable screening value could be found or generated for a substance. as noted in chapter 7, exceptions can include essential nutrients and other constituents naturally found in environmental media ( e. g., calcium, iron, magnesium ). - the community has expressed concern about a particular substance or exposure. even in cases where comparison values have not been exceeded, a more in - depth review of the health effects data might be needed to adequately address the community health concern. 8. 2 tools and resources needed to support an in - depth analysis in general, an in - depth analysis will require the examination and interpretation of reliable substance - specific health effects data ( toxicologic, epidemiologic, medical, and health outcome data ). much of the data will relate to dose - response relationships for the substance and pathways of interest. you also will determine whether health outcome data should or can be obtained ( i. e., information from pre - existing databases such as local or state disease registries ). in some cases, community or site - specific survey data might be available for evaluation as part of the public health assessment. atsdr ' s toxicological profiles serve


, information from pre - existing databases such as local or state disease registries ). in some cases, community or site - specific survey data might be available for evaluation as part of the public health assessment. atsdr ' s toxicological profiles serve as an important resource for health effects data. in most cases, these profiles will provide the information needed to support your analysis and draw public health conclusions. each peer - reviewed profile identifies and reviews the key literature that describes the toxicologic properties and adverse effects associated with a substance, including information on populations that might be unusually susceptible to a particular substance. these profiles also contain other substance - specific data, such as information on bioavailability and interaction with other chemicals. limitations and uncertainties of individual studies and the overall database are highlighted. the box below summarizes the content of atsdr ' s toxicological profiles. other compilations of toxicologic data include resources such as the u. s. environmental protection agency ' s ( epa ) integrated risk information system ( iris ) database, international agency for research on cancer ( iarc ) monographs, and national toxicology program ( ntp ), as well as some non - governmental resources. for more in - depth evaluations or in the absence of secondary sources such as those mentioned above, standard toxicology textbooks and peer - reviewed scientific journals of environmental toxicology or environmental health can be consulted. a listing of and links to such resources are provided at the end of this chapter. when identifying the most relevant and up - to - date sources of data to support your analysis, you might need to consult with the appropriate experts on your team. conducting a critical review of toxicologic or epidemiologic data requires specialized training and a thorough understanding of underlying scientific principles. similarly, a health physicist will need to assist in identifying appropriate resources for evaluating radiological hazards. the atsdr division of toxicology chemical manager is another resource in determining the status of any ongoing substance - specific research. if available secondary resources ( such as toxicological profiles ) have not been recently updated, it is important to identify the current state of the knowledge for a particular substance. ( while atsdr is continually reviewing substance - specific toxicologic data, some of the profiles could be a few years old. ) new information regarding observed effect levels or low - dose behavior might be important in interpreting site - specific doses ( see sections that follow ). 8. 3 evaluating studies on which exceeded health guidelines are based as described in chapter 7 and in appendix d,


) new information regarding observed effect levels or low - dose behavior might be important in interpreting site - specific doses ( see sections that follow ). 8. 3 evaluating studies on which exceeded health guidelines are based as described in chapter 7 and in appendix d, the health guidelines used in your screening analysis are generally extrapolated doses from observed effect levels in animal studies. health guidelines are usually based on a " critical " or " key " studygenerally, the study reporting the most sensitive endpoint at the lowest dose level. depending on the available data and the type of toxic response, observed effect levels are then adjusted by a series of uncertainty factors or through the use of statistical models to ensure that they are amply health - protective ( see figure 8 - 2 ). setting screening values at levels well below those known to cause harm is consistent with the fundamental concept of public health : prevention. when a health guideline is exceeded, a first step in understanding the public health significance of exceeding that guideline is to review and understand the basis for that guideline. understanding the applicability and strength of the study data will be a primary tool in evaluating whether site exposures are expected to cause harm. the goal of the analysis is to determine where site - specific doses lie in relation to the observed effects levels reported in the studies of interest and whether differences between study data and the exposure scenario being evaluated make health effects more or less likely. when developing health guidelines such as mrls, atsdr toxicologists and others extensively study the toxicologic literature and weigh the scientific data ( including the factors highlighted below ). reviewing the basis for an mrl and other health guidelines as part of this analysis in no way diminishes the importance of the health guideline ; rather, it serves as a means of gaining perspective on how strongly the supporting toxicologic data suggest that harmful exposures have occurred or might occur under your site - specific exposure conditions. two key steps in this analysis involve ( 1 ) comparing site exposure doses with observed effect levels reported in the critical study ( section 8. 3. 1 ) and ( 2 ) carefully considering study parameters in the context of site exposures ( see section 8. 3. 2 ). you will generally find information on the critical study in atsdr ' s toxicological profiles, in the section entitled health effects : relevance to public health and in the appendix presenting atsdr minimal risk levels and worksheets, or in epa ' s iris database. this step in the process involves comparing your substance - specific


toxicological profiles, in the section entitled health effects : relevance to public health and in the appendix presenting atsdr minimal risk levels and worksheets, or in epa ' s iris database. this step in the process involves comparing your substance - specific exposure dose to effect levels that are reported in the critical study used to derive the screening value that has been exceeded. ( 2 ) the health assessor should review the section of the toxicological profile in which the mrls are derived. the assessor should note whether the mrl is based on a human or animal study and whether the mrl is derived from a noael or loael. the assessor should then compare the site - specific exposure dose to the noael or loael. ( 3 ) if the site - specific exposures are well below a noael that is based on a human study, the likelihood for adverse health effects in the exposed population would be low. if, however, the noael is based on an animal study, exposure doses near the noael could be of concern because of uncertainty in the relative sensitivity of animals as compared to humans. ( in the absence of contrary information, it is prudent to assume that humans are more sensitive to the chemical than are animals. ) in some instances, an mrl is derived from a loael, rather than from a noael. the likelihood of adverse health effects increases as site - specific exposures approach a loael derived from either a human or animal study. because, by definition, loael doses cause adverse health effects, exposures that approach or exceed a loael are of concern and should be identified as a public health hazard. the health assessor should also consider the relevance of the mrl study to the site - specific exposure conditions and the exposed population. if the mrl was based on a noael in adults, and the population at the site includes a sensitive population such as children, the noael might not apply to all segments of the population. the assessor should also consider the exposure scenario of the mrl study. in experimental studies, administration of a high bolus dose of a chemical to an animal could have a different effect than low - dose chronic or intermittent exposures in humans. also, the assessor should consider the confidence in the mrl study ; if similar findings have been reported in other studies, confidence in the study is enhanced. section 8. 3. 2 of this chapter discusses other factors to consider when evaluating the relevance of the mrl study. as you review and integrate exposure


carcinogens should therefore include these classifications. the most current cancer classification information can be obtained from atsdr ' s comparison value tables, which are updated quarterly. more detailed information on the carcinogen classification for a specific substance can obtained through epa, iarc, or ntp. when discussing a chemical ' s carcinogenicity, explain in plain language what the different classification categories mean. for example, " human studies clearly link the substance of interest with certain cancers " or " while some animal studies have shown increased tumors after exposure to the substance of interest, human data do not suggest a link between the substance and cancer in humans. " note that atsdr evaluates the relevance of animal data to humans on a case - by - case basis. in the absence of compelling data to the contrary, however, a substance that has been shown to cause cancer in animals is considered to be carcinogenic in humans. - identifying effect levels or a point of departure. for known or potential human carcinogens, understanding the doses at which cancer effects might be expected under site - specific exposure conditions requires an understanding of the dose - response curve for the substance of interest. most available toxicologic data report cancer effects at doses much higher than those likely to be seen at hazardous waste sites. a first step therefore is to look at dose levels in this range of observation. in some cases ( similar to the benchmark dose described above ), toxicologists model available dose - response data to identify a " point of departure " ( or an estimated or modeled dose that is near the lower end of the observed range ). for example, a 5 or 10 percent effect level is often selected as the point of departure. this point of departure is then used as a stepping - off point for evaluating possible cancer effects at lower doses. as stated previously, various mathematical models have been developed to predict the potency of substances at low doses. these models are based on scientists ' understanding of the slope of the dose - response curve at high doses, and a series of assumptions about substance - specific behavior at doses below the range of observation ( e. g., below the point of departure ). when applying these models, scientists have by default historically assumed no threshold ( or linear dose - response ). as scientists learn more about the mechanism or mode of action by which carcinogens act, they are learning that this might not always be the case ( epa 2003a ; bogdanffy et al. 2001 ). ( 4 ) health assessors are not expected to


more about the mechanism or mode of action by which carcinogens act, they are learning that this might not always be the case ( epa 2003a ; bogdanffy et al. 2001 ). ( 4 ) health assessors are not expected to conduct the types of modeling analyses described above. however, considering the following questions will help the assessor understand the behavior of a particular carcinogen. this perspective is then communicated in the public health assessment document. - at what levels have cancer effects been reported in the literature? proceed with caution, but comparing site - specific doses with the lowest reported cancer effect levels ( cels ) can offer some perspective. realize that cels presented in the toxicological profiles represent only a snapshot of observed effect levels. as discussed above, it is not known whether lower doses will elicit a carcinogenic response. also, review epa ' s iris summaries and toxicological reviews to understand the basis for epa ' s cancer slope factors and the studies used to support risk assessment decisions, including identified effect levels or calculated points of - what is known about a substance ' s mode of action that might increase or decrease the likelihood of a cancer response at low doses? as emphasized in epa ' s guidelines for cancer risk assessment, knowing the manner in which cancer is initiated or promoted by a substance ( i. e., the mode of action ) will help in determining the following : ( 1 ) whether a " safe " level or threshold may exist for that particular substance, or ( 2 ) whether evidence or sufficient uncertainty exists to suggest that even at very low doses cancer potential cannot be ruled out ( epa 2003a ). in cases where low dose extrapolations have been used to quantify a theoretical estimate of cancer risk, it is critical to put the calculated risk into perspective when discussing site - specific cancer hazards. remember that any such estimate is based on several conservative assumptions to account for uncertainties. the true risk might be much lower ; it might even be as low as zero ( atsdr 1993 ; epa 2003a ). therefore, the health assessment team is encouraged to compare site doses with observed effect levels reported in the toxicologic and epidemiologic literature and discuss those site doses qualitatively in the context of issues presented throughout the remainder of this chapter. - at what levels have cancer effects been reported in the literature? proceed with caution, but comparing site - specific doses with the lowest reported cancer effect levels ( cels ) can offer some perspective. realize that cels presented in the


of this chapter. - at what levels have cancer effects been reported in the literature? proceed with caution, but comparing site - specific doses with the lowest reported cancer effect levels ( cels ) can offer some perspective. realize that cels presented in the toxicological profiles represent only a snapshot of observed effect levels. as discussed above, it is not known whether lower doses will elicit a carcinogenic response. also, review epa ' s iris summaries and toxicological reviews to understand the basis for epa ' s cancer slope factors and the studies used to support risk assessment decisions, including identified effect levels or calculated points of departure. evaluating carcinogens in this mannerassuming scientific data are available to support the analysisprovide the type of information needed to better communicate hazard potential to the community. a balanced discussion of what is known and not known will help provide more meaningful perspective to the community. as our understanding of substance - specific toxic action grows, public health conclusions can change. toxicologists at atsdr and at other agencies, such as epa, are reviewing available toxicologic information on an ongoing basis to help ensure the most accurate and scientifically defensible assessment of substance - specific hazards. the examples below illustrate the potential significance of identifying, understanding, and communicating the current understanding of a substance ' s toxic action. in examining tumor responses in mice exposed to chloroform, scientists have discovered that chloroform appears to work through a non - genotoxic mode of actionthat is, tumor responses are produced only at dose levels that result in cytotoxicity. therefore, noaels have been identified both via ingestion and via inhalation routes of exposure below which no increases in cancer would be expected ( jorgenson et al. 1985 ; larson et al. 1994 and 1996 ). as a result of these studies, epa has determined that the oral reference dose ( for non - cancer effects ) for chloroform is protective against an increased risk of cancer, and epa is currently working to revise its assessment for inhalation exposure ( epa 2001 ). using the newer inhalation data instead of the default linear dose extrapolation method could result in marked increases in predicted " safe " exposure concentrations. based on this newer understanding, larson et al. ( 1996 ) contrast a safe exposure concentration of 0. 01 parts per million ( ppm ) of chloroform in air to the current iris value of 0. 000008 ppm,


on this newer understanding, larson et al. ( 1996 ) contrast a safe exposure concentration of 0. 01 parts per million ( ppm ) of chloroform in air to the current iris value of 0. 000008 ppm, even after applying an uncertainty factor of 1, 000. on the other hand, remaining uncertainties related to arsenic behavior at low doses have prompted regulators to lower the drinking water standard for arsenic. the expertise of a toxicologist should be sought when seeking and interpreting any such data, but recognize that understanding the basis for the health guidelines that have been exceeded will, again, enable you to better communicate health hazard information. whenever reviewing dose - response data, an understanding of the underlying study is pivotal. if the dose comparisons discussed above reveal the need for further analysis, judging the relevance of the critical study used in developing a health guideline to the site - specific exposure situation will provide another piece of information to guide health conclusions. ( these factors are relevant when reviewing other studies as well ). as the health assessor, you will add site - specific knowledge and insight that will be critical to this evaluation. you should be able to perform the basic steps of a data review. assessing the relevance of available studies requires both technical expertise and professional judgment. numerous considerations beyond the scope of this guidance manual affect the quality of experimental data and its relevance to site - specific exposures. most relate to experimental design. this list, and associated examples, should not be viewed as a complete guide for evaluating all toxicologic studies but as a general guide to aid you in the context of the public health assessment process. again, work with the appropriate experts on your team when evaluating the importance and implications of such questions. in collaboration with the toxicologist and epidemiologist on your team, consider the following types of questions when evaluating how study features might make harmful effects more or less plausible. - is the critical study based on human or animal data? clearly, a study based on human data holds the greatest weight in describing relationships between a particular exposure and a human health effect. fewer uncertainties exist about potential outcomes documented in well - designed epidemiologic studies. exceeding a guideline value based on human data provides relatively strong evidence for the potential for harmful effects. similarly, falling below a noael reported in a human study could provide support for a conclusion that adverse effects are unlikely. however, before making this determination, the health assessor should consider the quality of the study and the size of the exposed group. similarities and differences


below a noael reported in a human study could provide support for a conclusion that adverse effects are unlikely. however, before making this determination, the health assessor should consider the quality of the study and the size of the exposed group. similarities and differences between available study data and your site - specific exposure conditions ( e. g., exposure route, chemical form ) should also be considered. - how relevant is the dosing method to site exposures? the relevance of the findings of an experimental study to environmental exposures will be influenced by how the test animal received its dose ( e. g., gavage / water, gavage / oil, water, food, or vapor ). often, the exposure route in experimental studies is different from the route by which people living near a site could be exposed. identify and discuss the differences to provide the reader with a sense of how differences can influence the likelihood of adverse health effects. for example, a laboratory study in which animals were administered a substance via gavage or drinking water might not directly apply to a soil - exposure scenario. this is because solubility is often an important component of how much and how quickly substances are absorbed, which might impact the nature of the toxic response. the form of the substance tested in water and gavage can differ considerably from the form present in soil. for similar reasons, a dietary animal study might not adequately represent exposures from drinking water. as another example, pregnant rats gavaged with oil solutions of trichloroethylene ( tce ) might be consuming much more tce per dosing than pregnant women drinking from tce - contaminated wells. the dose received by pregnant rats in oil could far exceed the dose even possible in drinking water because of differences in the solubility of tce in oil as compared to water. - how might dosing regimens influence the interpretation of the study data? < in addition to the method of dosing described above, the dosing regimen can influence the absorption and ultimately the effects observed in experimental studies. you will want to examine how closely, in relative terms, the study conditions match site - specific exposure conditions. some questions to ask include : were animals dosed continuously or intermittently? were animals dosed over the short or long term? for example, the same dose administered in the shorter term ( e. g., 28 days ) might produce different effects than those produced after a longer - term dose administration ( e. g., 90 days ). because different dosing


term? for example, the same dose administered in the shorter term ( e. g., 28 days ) might produce different effects than those produced after a longer - term dose administration ( e. g., 90 days ). because different dosing regimens can produce different effects or affect the severity of the observed effect, one can be more confident the more closely study data match site - specific conditions. if only acute or subchronic dose data are available, state the uncertainties of applying such data to longer - term exposures. - is the form of the toxicant in the selected study the same or different from the form detected at the site? the form or valence state of a substance can affect its bioavailability, its distribution within the body, and ultimately its toxicity. if study data are not available for the form of the substance present at your site, determine and explain in the pha whether the chemical form at your site could be more or less bioavailable, or more or less toxic, than the form used in the study. for example, the oral intermediate mrl for uranium is derived from a drinking water study. this is an important consideration when estimating doses for the soil ingestion pathway. a review of human data indicates that the fractional absorption of soluble uranium compounds is an order of magnitude greater than that of insoluble uranium compounds ( atsdr 1999a ). in weathered soils, insoluble uranium compounds will predominate. therefore, using the mrl to assess exposure to uranium in soil would be overprotective, because of the reduced bioavailability of uranium in soil as compared to water. as another example, most arsenic in fish is in an essentially non - toxic organic form known as arsenobetaine ( fish arsenic ). inorganic arsenic, which is considerably more toxic, makes up only a small amount ( 120 % ) of total arsenic in fish ( atsdr 2000 ; francesconi and edmonds 1997 ; fda 1993 ). therefore, if you were evaluating arsenic exposures via fish ingestion, you would need to account for this factor. - are the effects observed in animals expected in humans? if dose levels from animal studies ( e. g., in mice, rats, monkeys ) are being used to evaluate site exposures, determine whether any human or any in vitro studies are available that suggest a similar effect in humans. in addition, metabolism or mechanistic data, if available, could provide insight as to whether observed


monkeys ) are being used to evaluate site exposures, determine whether any human or any in vitro studies are available that suggest a similar effect in humans. in addition, metabolism or mechanistic data, if available, could provide insight as to whether observed effects might be unique to, or different in, the study animal as compared to humans. if such data do not exist, assume that similar effects would occur in humans. some possible scenarios include : the metabolism of a chemical in animals could produce more or less toxic intermediates than in humans ; the metabolism in humans could occur by another pathway and produce more toxic, non - toxic, or less toxic intermediates ; or toxic intermediates could be produced at the high levels of exposures administered in the animal studies, but not at lower exposure levels. ( see also discussion on toxicokinetics and mechanistic data in sections 8. 5. 1 and 8. 5. 2, respectively ). - how relevant are observed health endpoints to specific community health concerns? while health - based guidelines are typically designed to be protective of the most sensitive effect, it is important to familiarize yourself with the range of effects associated with a given chemical in the dose range of concern. this could provide added perspective as well as help in addressing community health concerns. for example, if an mrl is based on increased kidney weight in rodents and the community is concerned primarily about blood - related disorders, you might want to look beyond the critical study for substance - specific data related to hematologic effects following exposure to the substance of concern ( see section 8. 4 ). - does the bioavailability of the substance differ in the study matrix versus the environmental matrix being evaluated? the bioavailability of a contaminant depends on its chemical properties as well as properties of the matrix. the bioavailability of a substance influences how much is absorbed by the human body and ultimately the potential for harmful effects. bioavailability should be factored into the analysis when there is evidence that the chemical form at the site is more or less bioavailable than is the chemical form used in the studies being used for comparison purposes. the bioavailability of a compound is discussed in toxicokinetics section of the toxicological profile. substances in solid matrices ( e. g., soil ) might be less well absorbed while passing through the digestive tract than would the same substances in water. this could be due to the solubility of the substance and the property of the matrix. some


solid matrices ( e. g., soil ) might be less well absorbed while passing through the digestive tract than would the same substances in water. this could be due to the solubility of the substance and the property of the matrix. some forms of a salt can bind tightly to soil, thereby reducing its bioavailability. for instance, some forms of arsenic bind tightly to soil and are therefore not readily absorbed in the human digestive system. on the other hand, the same form of arsenic in drinking water can be released from the matrix and more readily absorbed ( alexander 2000 ). ultimately, the rate of substance dissolution will determine its uptake and availability ( hardman et al. 1995 ). - what uncertainties / limitations exist? identify any problems or limitations with the studies used to support your analysis. in most cases, uncertainties and limitations will be discussed in the health effects section of the toxicological profiles and in the discussion of the mrl derivation. iris summaries also discuss uncertainties and confidence in the critical studies evaluated by epa. the pha should describe any limitations, uncertainties, and data gaps found in the available literature. describe in qualitative terms the uncertainty factors used in the development of health guidelines. also discuss the level of confidence in the studies as well as their overall applicability to site - specific exposures. the higher the confidence or level of certainty, the more weight the study will hold in your analysis. 8. 4 reviewing other dose - response data as previously discussed, health guidelines are generally based on the lowest observed adverse effect levels reported in the literature, very often from a single study. in addition to the critical study, other studies can provide substance - specific, dose - response data. for substances of potential concern at a given site, the health assessor would never be expected to perform an exhaustive review of these studies. however, reviewing the larger toxicologic and epidemiologic database ( e. g., the levels of significant exposure summarized in the toxicological profiles ) provides additional supporting evidence for public health assessment discussions. in the in - depth analysis, one looks beyond single points on the dose - response curve to gain a fuller understanding of the range of effects and effect levels observed in experimental studies. both the shape and slope of the dose - response curve can help explain where site - specific exposures lie in the larger scheme of things. this will often help provide the perspective community members seek, and it will help you decide which, if any, harmful effects might


and slope of the dose - response curve can help explain where site - specific exposures lie in the larger scheme of things. this will often help provide the perspective community members seek, and it will help you decide which, if any, harmful effects might be possible. in some cases, consistent findings might be seen across studies. for other substances, findings might be more disparate. the most important thing for the health assessor to keep in mind is how to describe in plain language what is known and not known about the toxicity of a particular substance. questions to consider include : - where does the noael or loael for the critical study fall in relation to other studies? although the critical study will weigh most heavily in your analysis, it might be helpful to describe the similarity or disparity of dose levels and health endpoints observed across studies. your pha should introduce information that will further support your discussion and eventual conclusions. for example, many of the reported effect levels in other studies for the substance of interest may be in the in the same general range as the critical study, strengthening the evidence that effects might be seen in that dose range. - if the health guideline is based on animal data, do any human data exist that shed more light on the issue? if extensive epidemiologic data are available for a particular substance, these data will likely have been reviewed and considered in the derivation of the health guideline for that substance ( e. g., the mrl for methyl mercury ). however, as a minimum, available epidemiologic data can be used to augment the findings of animal studies. for example, an occupational study can show that exposure to a particular substance is associated with the same toxic endpoint seen in animal studies. this observed species concordance would provide greater weight to the available animal dose - response data used to evaluate human health effects. recognize the importance of not taking dose - response data at face value. the criteria described in section 8. 3. 2 should be considered carefully. remember, the critical study has been identifiedafter careful review of the scientific literatureas the best for developing protective health guidelines. the purpose of this exercise is not to discredit that effort, but to encourage consideration of the bigger picture. the exposure levels and associated outcomes, when available, can sometimes be used for comparison purposes with site exposures. for example, take the following scenario : community members are concerned about low levels ( 2 parts per billion [ ppb ] ) of a particular contaminant


associated outcomes, when available, can sometimes be used for comparison purposes with site exposures. for example, take the following scenario : community members are concerned about low levels ( 2 parts per billion [ ppb ] ) of a particular contaminant in drinking water that they have been drinking for approximately 10 years. they believe leukemia rates are elevated. two independent studies of community drinking water supplies with 100 ppb of the same contaminant revealed no elevated leukemia or any other cancers in populations exposed for 30 years. in this case, the epidemiologic data might provide evidence supporting the fact that site exposures are unlikely to produce cancer effects at site exposure levels, notwithstanding possible study shortcomings. furthermore, an understanding of toxicologic and epidemiologic data can help determine the biologic plausibility of a particular health outcome. note that, depending on the community concern and other factors, an evaluation of health outcome data can be considered in such a case ( see section 8. 6. 1 ). because of the inherent limitations and uncertainties associated with environmental epidemiologic evaluations ( generally due to the lack of adequate exposure data or sample size ), epidemiologic data described in a toxicological profile or other sources should be used with caution. the health assessor should therefore call upon an epidemiologist to assist in evaluating the applicability and usability of literature - based or site - specific epidemiologic data. criteria have been established to guide epidemiologists in evaluating the strength of human data and should be kept in mind when you review and communicate such data in the context of your site - specific data ( see text box below ). 8. 5 evaluating other substance - specific factors that can increase or decrease the potential for harm as depicted in figure 8 - 3, multiple factorsother than the detected environmental concentration or exposure doseinfluence whether an exposure could result in harmful health effects and what the type and severity of those health effects will be. a substance will only produce adverse or toxic effects if it or its metabolites reach specific sites in the body at a concentration and over a duration sufficient to produce an adverse effect. whether exposure could lead to an adverse health outcome depends on the duration and characteristics of exposure and on the characteristics of the receptor population ( e. g., developmental stage, existing disease state, genetics ) that could make them more or less susceptible to site - related exposures. these factors are generally considered in the development of health


of exposure and on the characteristics of the receptor population ( e. g., developmental stage, existing disease state, genetics ) that could make them more or less susceptible to site - related exposures. these factors are generally considered in the development of health guidelines and during the screening analysis, but might need to be examined more closely at this stage of the public health assessment process and described in your pha narrative. this section provides a brief overview of these factors and how they could weigh into your public health conclusions. substance - specific toxicokinetic or pharmacokinetic properties ( e. g., absorption, distribution, metabolism, and elimination ) largely influence whether a substance will reach a target organ and produce a toxic effect. if available, such information can be obtained from the toxicological profile or other data sources for toxicokinetic summaries. determine what is known and not known about the extent to which a substance is absorbed. also, how it is distributed through the bloodstream, changed to different forms, excreted, or ultimately delivered to target organs. when available, toxicokinetic data can be used in various ways to support your health effects evaluation. for example, it can used in interpreting the relevance of animal studies to human exposuresthat is, by determining whether any distinct differences between animals and humans have been documented. for example, does the metabolism of the substance in animals produce more or less toxic intermediates than in humans? is the substance absorbed more or less in animals compared to humans? note that, in absence of data to the contrary, bioavailability is assumed to be the same in animals and humans under similar exposure conditions. for some substances, quantitative data can allow you to compare the bioavailability of a substance in experimental animals and humans. knowledge continues to grow on how various toxic substances produce biologic changes and the significance of those changes. in fact, this growing knowledge is modifying how human health hazards are assessed. while this type of analysis is best left to the toxicologists, reviewing documentation ( e. g., toxicological profiles, iris ) on the nature of biologic changes triggered by a particular substance can be helpful in evaluating the behavior of that substance at low doses. further, understanding the basic or specific biologic changes that ultimately lead to clinical disease in a test animal can aid in determining how well animal models might predict the same type of adverse effect in humans. a toxicologist might ask, for example, if the animal mode of action is plausible in humans, taking into consideration


lead to clinical disease in a test animal can aid in determining how well animal models might predict the same type of adverse effect in humans. a toxicologist might ask, for example, if the animal mode of action is plausible in humans, taking into consideration the kinetic and dynamic factors discussed above. for a limited number of chemicals where biologic uptake and mode of action have been well studied and defined, physiologically based pharmacokinetic ( pbpk ) models have been developed to estimate dose levels in various body compartments and organs ( e. g., lead ). these models involve a series of mathematical equations that describe the pharmacokinetics of a chemical. inputs into the models include the exposure dose and model parameters, such as tissue volumes, blood flow rates, partition coefficients, and metabolic rates. the output is the predicted internal dose ( or target tissue dose ). pbpk models are also beginning to be used to evaluate chemical mixtures ( atsdr 2001a ; krishnan et al. 2002 ). pharmacodynamic ( pd ) models are also available ; these mathematical models describe the quantitative relationship between the target tissue dose and cellular and molecular changes associated with adverse health effects. increasingly, pd models account for damage, repair, and compensation, and predict dose - response over a range of doses, both within and between species. when pbpk or pd models are available and are applied, they can help to reduce the uncertainty in the health evaluation. also, the models eliminate the need for cross - species extrapolation because they can account for differences in rates of biologic processes. for some substances, toxicologists have used such models in deriving health guideline values. the data used to support the model ( e. g., metabolism and distribution data ) can provide added perspective of how closely linked a particular dose might be to an adverse health effect. although health assessors would not be expected to apply all of these types of models, an understanding of the general underlying principles can support the site - specific analysis, as described above. models also exist to estimate the radiation dose to specific organs and tissues, as well as total body dose. like chemical exposures, ionizing radiation can produce many different effects, depending on ( 1 ) the type of radiation, ( 2 ) the radionuclide and its metabolic products, and ( 3 ) the dose received by the critical or most sensitive organ. when evaluating exposures to radiological contamination, enlist the help of a health physicist.


the type of radiation, ( 2 ) the radionuclide and its metabolic products, and ( 3 ) the dose received by the critical or most sensitive organ. when evaluating exposures to radiological contamination, enlist the help of a health physicist. see text box below for special considerations for radiological contaminants. some substances have been shown to cause greater harm in particular populations or when exposure occurs at a particular point in life ( e. g., fetal development ). it is atsdr policy that children ' s health issues must be considered at all sites ( atsdr 1998 ). it is important to remember that sensitive populations are considered when mrls and other health - based comparison values are developed. an uncertainty factor ( e. g., a factor of 10 ) is generally applied to help ensure sensitive populations are amply protected. in addition, comparison values are developed to specifically account for children ' s exposures. identifying or accounting for potentially sensitive or more highly vulnerable populations should also be a key component of your exposure pathway analysis ( chapter 6 ) as you estimate site - specific doses ( chapter 7 ). thus when comparison values are not exceeded, health assessors can be confident that it is highly unlikely that even the most sensitive populations would be adversely affected. however, when site - specific doses exceed comparison values, site - and substance - specific factors should be re - examined to evaluate to what extent, if any, a particular population is at increased risk of harm. information on potentially sensitive populations can be found in the toxicological profiles in the section titled, populations that are unusually susceptible. as stated, atsdr places particular emphasis on children as a potentially sensitive population. for information on children ' s susceptibility, the health assessor should read those sections of the toxicological profiles that specifically discuss the susceptibility and exposure of children to chemicals ( children ' s susceptibility and exposures of children ). characteristics of certain populations might make them more sensitive to environmental exposures because of underlying disease, other physiologic factors, or non - site related exposures. many of these issues should be first addressed and highlighted during the exposure pathway and screening analyses ( see chapters 6 and 7 ). at this point in the analysis, you need to determine whether special characteristics of the substance and of the site community might affect public health conclusions. - age. children differ from adults in their exposures and can differ in their susceptibility to certain hazardous substances. understanding when exposures occurred during


to determine whether special characteristics of the substance and of the site community might affect public health conclusions. - age. children differ from adults in their exposures and can differ in their susceptibility to certain hazardous substances. understanding when exposures occurred during critical periods of development is therefore important. the box below highlights some special considerations when evaluating children ' s health issues. note that atsdr and others continue to research the significance of early - life exposures to toxic substances, both for cancer and non - cancer outcomes. much of the impetus for such an approach is the growing knowledge and understanding of how a substance exerts its effect ( i. e., its mode of action ) and how, if exposure occurs during early - life stages, a particular mode of action can increase the risk of a toxic response ( epa 2003b ). - sex. some substance - specific adverse health effects can be mediated by hormonal influences and other factors that are sex - linked. in general, sex - linked differences in toxic susceptibilities have not been extensively investigated. however, it is well documented that, because of various physiologic modifications in the body that occur during pregnancy, pregnant women are often at significantly greater risk from exposure to beryllium, cadmium, lead, manganese, and organophosphate insecticides than areother members of the general population ( calabrese 1986 ). - genetic background or ethnicity. some research suggests that certain genetic factors can increase the risk of developing chemically - induced health effects, though further research is needed ( calabrese 1994 ). factors that can affect the susceptibility of exposed groups include acetylation phenotype ( i. e., fast versus slow acetylators ), sickle cell trait, and glucose - 6 - phosphate ( g6pd ) deficiency ( rios et al. 1993 ). in addition, individual variability in the induction of metabolic enzymes could cause people to respond differently to the same environmental exposure. for health assessment purposes, the susceptibility of the most sensitive subgroups should be considered. - health and nutritional status. understanding the location and characteristics of subgroups, such as the elderly and those of lower socioeconomic status, will help identify pre - existing health conditions ( e. g., asthma, nutritional deficiencies ) that might influence the impact of site exposures. locations of schools, playgrounds, recreational areas, retirement homes, or convalescent homes on or near a site should be


existing health conditions ( e. g., asthma, nutritional deficiencies ) that might influence the impact of site exposures. locations of schools, playgrounds, recreational areas, retirement homes, or convalescent homes on or near a site should be carefully noted as important indicators of the presence of potentially sensitive populations. - cultural practices. various practices ( e. g., ceremonies among american indian and alaska native populations, subsistence fishing, medicinal use of plants ) can lead to increased exposures. these factors should be considered as part of your exposure assessment and when estimating site - specific exposure doses ( see chapters 6 and 7 ). the literature suggests that elderly populations may have significantly heightened susceptibility to some contaminants because of lower functional capacities of various organ systems, reduced capacity to metabolize foreign compounds, and diminished detoxification mechanisms. it is difficult to generalize, however, due to variations across individuals and different rates in biological system breakdown ( hardman et al. 1995 ). another important consideration is that older individuals may have much different exposures than younger adults and children. the approaches outlined in this manual focus largely on evaluating chemical - specific and pathway - specific exposures. that is, health effects are examined for individual chemicals for specific exposure pathways ( e. g., ingesting benzene in drinking water ). in reality, exposures can involve multiple chemicals and can occur through more than one exposure pathway. approaches for evaluating the effect of multiple pathways are discussed in chapter 7. this section highlights how to approach multiple - chemical scenarios. the health impact of exposure to chemical mixtures can be of particular concern at hazardous waste sites, since most contain multiple chemical contaminants. while in many cases it might suffice to evaluate exposures on a chemical - by - chemical basis, in some cases you might need to examine the combined action of chemicals ( e. g., additive, antagonistic, synergistic, and other interactive effects ). a first step in understanding the potential significance of multiple chemical exposures is to read the interactions with other chemicals section of the toxicological profile about any known interactions among the substances detected at your site. these profiles can provide insight regarding what is known and what is not known about interactions among various pollutants. for many chemicals, however, information on toxic interactions is lacking, and the available literature focuses on the effects of chemical interactions at exposure doses that are much higher than those that are typically encountered at hazardous waste sites. furthermore, even though limited information for


. for many chemicals, however, information on toxic interactions is lacking, and the available literature focuses on the effects of chemical interactions at exposure doses that are much higher than those that are typically encountered at hazardous waste sites. furthermore, even though limited information for some chemical mixtures is available, no empirical data set could account for the infinite array of chemicals in varying proportions that can be found at sites. when conducting public health assessments, it is particularly important to understand potential toxic interactions at environmentally relevant doses of chemicals. however, relatively few studies have been conducted to assess toxic interactions in these low dose ranges. a series of important studies on the toxicity of low dose chemical mixtures was conducted by the tno nutritional and food research institute in the netherlands ( jonker et al. 1990 ; jonker et al. 1993 ). in these experiments, rats were dosed with mixtures of chemicals at doses near their individual noaels and loaels. the results of these experiments indicated that there was no discernable toxic response until the dose levels of the individual chemicals approached or exceeded their individual thresholds. however, when the chemicals were administered at their individual loael doses, there was clear evidence of additive toxic effects. furthermore, additive toxicity was observed even though the chemicals had different mechanisms of toxicity. other studies have provided evidence that exposure to chemical mixtures, in which the chemicals were administered at doses that were near their individual thresholds, can produce additive toxic effects. for example, rats exposed to a mixture of subthreshold doses of 1, 1, 1 - trichloroethane, trichlorethylene, and tetrachloroethylene experienced signs of liver toxicity ( stacey 1989 ). in an oral feeding study, rats were dosed with cadmium and lead. neither metal, by itself, significantly affected hemoglobin or hematocrit levels ; but when the metals were administered as a mixture, significant decreases in these parameters were observed ( mahaffey and fowler 1977 ). however, there is no evidence of additive toxicity from exposure to chemical mixtures when the individual chemicals are administered at doses that are well below their individual thresholds ( seed et al. 1995 ; wade et al. 2002 ). nevertheless, the threshold doses for many toxic endpoints in animals are not well defined. therefore, it is prudent for the health assessor to consider the potential for toxic effects from exposure to chemical mixtures at all sites. inthe health assessment, the assessor should indicate that he has evaluated exposures


are not well defined. therefore, it is prudent for the health assessor to consider the potential for toxic effects from exposure to chemical mixtures at all sites. inthe health assessment, the assessor should indicate that he has evaluated exposures to chemical mixtures and considered the potential for chemical mixture interactions. as part of this evaluation, the health assessor should calculate a hazard index ( hi ) for the mixture of chemicals at a site. a hi is defined as the sum of the quotients of the estimated dose of a chemical divided by its mrl or comparable value. in mathematical terms, | + | |..... | | dosen for additional information on calculating an hi, see atsdr ' s guidance manual for the assessment of joint action of chemical mixtures. this manual is available on cd - rom and on the atsdr web site. if the hi is less than 1. 0, it is highly unlikely that significant additive or toxic interactions would occur, so no further evaluation is necessary. if the hi is greater than 1. 0, then further evaluation is necessary as described below. for chemical mixtures with a hi greater than 1. 0, the assessor should compare the estimated doses of the individual chemicals to their noaels or comparable values. if the dose of one or more of the individual chemicals is within one order of magnitude of its respective noael ( 0. 1 x noael ), then there is a potential for additive or interactive effects. under such circumstances, the assessor should conduct an in - depth mixtures evaluation as described in atsdr ' s guidance manual for the assessment of joint action of chemical mixtures. if the estimated doses of the individual chemicals are less than one - tenth of their respective noaels, then significant additive or interactive effects are unlikely, and no further evaluation is necessary. in some instances, however, the assessor might choose to evaluate further the potential for additive or interactive effects because the chemicals in the mixture have the same target organ, have the same mechanism of action, or for other reasons. in these instances, the assessor can conduct an in - depth quantitative mixtures analysis as described above. another valuable resource for information on chemical mixtures is the interaction profiles for priority chemical mixtures. atsdr is developing these profiles for chemical mixtures that are of special concern to atsdr, such as persistent chemicals found in fish ( atsdr 2002 ). these documents use a weight - of - evidence approach to evaluate the influence


. atsdr is developing these profiles for chemical mixtures that are of special concern to atsdr, such as persistent chemicals found in fish ( atsdr 2002 ). these documents use a weight - of - evidence approach to evaluate the influence of interactions in the overall toxicity of the mixture. the documents also develop target organ doses that can be used to evaluate the impact of the chemical mixture on different target organs. 8. 6 evaluating site - specific health effects data another line of evidence that can provide additional site - specific perspective is the availability of meaningful health outcome data or human exposure data. in certain cases, data from health outcome data evaluations can provide evidenceranging from weak to strongof plausible associations between substance - or site - specific exposures and human health effects. in some cases, biologic data ( e. g., site - specific substance concentrations in blood or urine ) collected as part of exposure investigations, might be available and offer some insight on the extent of actual exposure ( beyond the exposure - dose estimates generated from environmental concentrations ). in rare cases, individual medical reports might be available, documenting symptoms or the results of clinical examinations. note, however, that in most cases there is a lack of data to correlate biologic levels with health effect levels. this section describes how to determine whether such data can help support your public health conclusions. this section provides guidance to health assessors for addressing health outcome data in the public health assessment process. health outcome data are existing data that measure disease mortality or morbidity. health outcome data analyses or reviews are descriptive epidemiologic analyses. in all public health assessments, atsdr is required by the superfund law to consider the evaluation of mortality and morbidity data ( e. g., health outcome data ). the law indicates that a public health assessment should include relevant health outcome data analyses when exposure to site contaminants could have resulted in the development or exacerbation of health effects. the guidance presented below reflects the deliberations of the atsdr work group, whose members examined the decision criteria used to evaluate the appropriate use of health outcome data in the public health assessment process. decisions about how to use or analyze health outcome dataor whether to use it at allshould be made with the assistance of various disciplines. to reach a prudent decision, a health assessor might include input from epidemiologists, statisticians, toxicologists, community involvement specialists, health educators, and environmental scientists such as engineers or


made with the assistance of various disciplines. to reach a prudent decision, a health assessor might include input from epidemiologists, statisticians, toxicologists, community involvement specialists, health educators, and environmental scientists such as engineers or geologists. inclusion of a health outcome data evaluation in a public health assessment can achieve the following if it is determined that it is appropriate to include such an evaluation : - comparison of the occurrence of disease between a population potentially exposed to site contaminants and an appropriate reference population, such as the county, the state, or the united states. - assistance in addressing community concerns about the occurrence of disease in potentially exposed individuals. - identification of the potential need for follow - up health actions such as exposure investigations, analytical epidemiologic studies, or health surveillance. traditionally, at the outset of the public health assessment process, the health assessor in concert with the site team gathers community concerns and informs community members about atsdr products and services. during this period the site team should provide to community members information about the utility of analyzing health outcome data. specifically, community members should be informed of how atsdr uses health outcome data, when it is available, and the criteria and rationale used to determine whether a health outcome data evaluation would enhance the public health assessment decision - making process. therefore, regardless of whether health outcome data are used in the public health assessment itself, the analysis of the criteria for each site, as described below, is in essence the first step in the evaluation of health outcome data. the team should use the answers to the following questions as a guide in determining whether a public health assessment should include analysis and interpretation of site - related health outcome data. see also figure 8 - 4. the criteria below focus on site - related exposure considerations only. regardless of what path you follow, your pha discussions must clearly describe the rationale for the decision, and how your exposure evaluation factored into the decision. in some cases, community concern about illness in their community could be a sufficient trigger to pursue health outcome data, even in the absence of a potential or completed exposure pathway. assuming data are available for the disease ( s ) of concern and the geographic unit under evaluation, a health outcome data evaluation would determine whether disease rates are elevated in the community. while no possible site - specific link might exist, information regarding the presence or absence of elevated disease rates could either help allay fears or identify a disease trend in the community warranting follow - up. the decision to proceed