Geoscience

Radiocarbon (14C) dating (1, 2) is widely used to determine the ages of samples that are less than about 50,000 years old. Natural radiocarbon is mainly formed in Earth's stratosphere through the interaction of neutrons produced by cosmic rays with 14-nitrogen. However, the rate of radiocarbon production is not constant (3), nor is its partitioning among the atmosphere, terrestrial biosphere, and oceans. After local corrections [see, for example, (4-6)], radiocarbon ages must therefore be calibrated to obtain ages on an absolute time scale (7). For decades,

The authors are at the LLNL Center for Accelerator Mass Spectrometry, University of California, Livermore, CA 94550, USA. T. P. Guilderson is also at the Institute of Marine Science and Department of Ocean Sciences, University of California, Santa Cruz, CA 95064, USA. E-mail: [email protected]

(frequently referred to as ischemia). A ceftri-axone-mediated increase in glutamate clearance also decreased neuronal death induced by oxygen deprivation, at least in cell culture.

The encouraging preclinical data from the ALS mouse and other models ofneurological disease have prompted a clinical trial combining all three phases. This is expected to begin this spring with a safety and efficacy study of ceftriaxone in the treatment of ALS. The data generated by the consortium represent a phenomenally quick turnaround from initial drug screening (started in early 2002) to actual use in patients. This reflects the major advantage of screening FDA-approved drugs whose safety profiles are already known. Even more encouraging for the Rothstein et al. findings are the excellent safety profiles of the P-lactam antibiotics in humans. Drug toxicity is costly and time-consuming to exclude and, in the end, is often the Achilles' heel that sinks the development of promising new therapeutics. In addition, spotting unwanted side effects is challenging even after undertaking multiple preclinical and clinical trials. This lesson was learned most recently with the realization of the increased risk of stroke and heart attack in people taking commonly prescribed anti-inflammatory drugs (8). Against this backdrop are the P-lactam antibiotics, first identified with the discovery of penicillin in 1928 and now among the most widely used modern pharmaceuticals. Although data about the safety of long-term the radiocarbon community has adopted international calibration standards, most recently IntCal98 (8). Here, we discuss the inherent limitations faced when using radiocarbon dates to derive calendar ages.

From modern day to 11,800 years ago, IntCal98 is based on sets of tree-ring chronologies that each cover several thousand years and together provide an annually resolved, nearly absolute time frame. These data set a quality standard against which other proposed calibration datasets can be judged. Prior to 11,800 years ago, IntCal98 is based on marine data and contains additional assumptions and uncertainties associated with the translation of marine data into atmospheric radiocarbon values.

Here we examine how precisely calendar ages can be determined from individual radiocarbon dates. We focus on the tree-

ceftriaxone use still need to be collected, the best predictor of safety is a long history of safe use in humans. Our vast experience with short-term P-lactam antibiotic treatment predicts that very few problems should arise over the long term.

The discovery of new modes of action for the P-lactam antibiotic family offers two additional lessons for biomedical researchers. The first is unproven but predictable: A systematic screen of easily accessible chemical compounds already approved by the FDA may reveal common therapeutics with new potential applications. The second is more surprising: Some of these compounds may act by transcriptional induction of key proteins. Searching for transcriptional up-regulation is not an approach generally thought attractive in drug screening. With that in mind, last century's miracle drug, the P-lactams, may well rise to one of the big challenges of this century: slowing the progression of neurological diseases whose treatment has so far evaded the world's best efforts.

References

3. P. R. Heath, P. J. Shaw, Muscle Nerve 26,438 (2002).

4. J. D. Rothstein et al.,Ann. Neurol. 28,18 (1990).

5. J. D. Rothstein et al.,Ann. Neurol. 30,224 (1991).

6. D. S. Howland et al., Proc. Natl. Acad. Sci. U.S.A. 99,

7. L. I. Bruijn et al.,Annu. Rev. Neurosci. 27,723 (2004).

10.1126/science.1109027

ring section of the IntCal98 calibration curve. Between 0 and 8000 years before the present (B.P.), the error in this curve is often less than 20 years, and—except for a few brief intervals—it is less than 30 years over the past 11,800 years. But as we will show, the range of statistically possible calendar ages, or calibrated age ranges, corresponding to any particular radiocarbon date can be larger or smaller, depending on where it falls on the curve.

We have linearly interpolated the Int-Cal98 curve at intervals of 20 calendar years and determined the radiocarbon dates that correspond to the calendar ages. We then calibrated these resampled radiocarbon ages using CALIB v4.4 (4) assuming an uncertainty of ±40 radiocarbon years, which is currently typical of routine dating (calibration 1). We performed a second calibration with a constant uncertainty of ±15 radiocarbon years, which is typical of the IntCal98 tree-ring data (calibration 2).

The calibrated age range waxes and wanes (see the first figure) as a result of variations in the atmospheric 14C/12C ratio. On average, the 1a calibrated age range is 180 years (minimum 30 years, maximum 529 years) for calibration 1 and 140 years

The Boon and Bane of Radiocarbon Dating

Tom P. Guilderson, Paula J. Reimer,Tom A. Brown

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